Born in Chicago, Silverstein began drawing at age five by tracing the works of Al Capp, as he later recalled, "The first thing I did was copy Al Capp. He really influenced me. It was the most wondrous thing for me. Al Capp knew how to draw people, shapes, bodies, hands. He knew how to draw well, so I learned how to draw well." He was also influenced by the style of gag cartoonist Virgil Partch. He told Jean Mercier of Publishers Weekly: "When I was a kid—12 to 14, around there—I would much rather have been a good baseball player or a hit with the girls, but I couldn't play ball. I couldn't dance. Luckily, the girls didn't want me. Not much I could do about that. So I started to draw and to write. I was also lucky that I didn't have anybody to copy, be impressed by. I had developed my own style; I was creating before I knew there was a Thurber, a Benchley, a Price and a Steinberg. I never saw their work till I was around 30. By the time I got to where I was attracting girls, I was already into work, and it was more important to me. Not that I wouldn't rather make love, but the work has become a habit."He attended the Art Institute of Chicago but left after one year. He was first published in the Roosevelt Torch (a student newspaper at Roosevelt University). In the military, his cartoons were published in Pacific Stars and Stripes, where he had originally been assigned to do layouts and paste-up. His first book, Take Ten, a compilation of his military Take Ten cartoon series, was published by Pacific Stars and Stripes in 1955.

Returning to Chicago as a civilian, Silverstein began submitting freelance cartoons to magazines while also selling hot dogs at Chicago ballparks, setting a record for the number of hot dogs sold at the Thursday night games. His cartoons began appearing in Look, Sports Illustrated and This Week.

Mass-market paperback readers across America were introduced to Silverstein in 1956 when Take Ten was reprinted by Ballantine Books as Grab Your Socks! with a foreword by Bill Mauldin.

In 1957, he became one of the leading cartoonists in Playboy, which sent him around the world to create an illustrated travel journal with reports from far-flung locales. During the 1950s and 1960s, he produced 23 installments of his regular "Shel Silverstein Visits..." feature for Playboy. Employing a sketchbook format with typewriter-styled captions, he documented his own experiences at such locations as a New Jersey nudist colony, the Chicago White Sox training camp, San Francisco's Haight-Ashbury district, Fire Island, Mexico, London, Paris, Spain and Africa. In a Swiss village, he drew himself complaining, "I'll give them 15 more minutes, and if nobody yodels, I'm going back to the hotel." These illustrated travel essays were collected by the publisher Fireside in Playboy's Silverstein Around the World (2007), with a foreword by Hugh Hefner and an introduction by music journalist Mitch Myers.

His best known cartoon of the 1950s was featured on the cover of his next cartoon collection, Now Here's My Plan: A Book of Futilities, published by Simon & Schuster in 1960. Silverstein biographer Lisa Rogak wrote:

The cartoon on the cover that provides the book's title would turn out to be one of his most famous and often-cited cartoons. In the cartoon, two prisoners are chained to the wall of a prison cell... Both their hands and feet are shackled. One says to the other, "Now here's my plan." Shel was both fascinated and distressed by the amount of analysis and commentary that almost immediately began to swirl around the cartoon. "A lot of people said it was a very pessimistic cartoon, which I don't think it is at all," he said. "There's a lot of hope even in a hopeless situation. They analyze it and question it. I did this cartoon because I had an idea about a funny situation about two guys."

Silverstein's cartoons appeared in every issue of Playboy from 1957 through the mid-1970s, and one of his Playboy features was expanded into Uncle Shelby's ABZ Book (Simon & Schuster, 1961), his first book of new, original material for adults. Because some were confused whether it was for adults or children, the 1985 reprint had a conspicuous cover label, "A Primer for Adults Only".

His stance on art and creativity was revealed in a 1963 Aardvark magazine interview:

I think that if you’re truly creative, you can work in certain related fields of creativity, but then there are others that are beyond you. For instance, a man who works well with words might work as a writer and as a poet and as a lyricist. But if he tried to work in sculpture, he might get absolutely nowhere. And a guy who is very visual might easily work in painting and drawing, could also work in costume design, if he leaned that way, could work in stage setting, and in those related fields. I do believe that a person who is truly observant in one of the arts will be truly observant and sensitive in the others as well, but it’s his ability to express these things that would limit him. I believe that a man who is a sensitive painter is sensitive to life, and therefore would be sensitive as a writer or as a storyteller, but having the ability to write is something more than merely seeing. Having the ability to paint is something more than merely seeing the colors, seeking the form. It’s in execution, in skill.

Silverstein's editor at Harper & Row (now HarperCollins), Ursula Nordstrom, encouraged Silverstein to write children's poetry. Silverstein said that he never studied the poetry of others and therefore developed his own quirky style, laid back and conversational, occasionally employing profanity and slang. In the Publishers Weekly interview, he was asked how he came to do children's books:

He is a strong, well-muscled, fit-looking man who wears blue jeans and a big cowboy hat. Though he has to be into his 40s (he's a Korean War veteran), he is also totally in touch with the contemporary scene... How, then, PW wanted to know, had he decided to get into children's books? "I didn't," Shel said, "I never planned to write or draw for kids. It was Tomi Ungerer, a friend of mine, who insisted—practically dragged me, kicking and screaming, into Ursula Nordstrom's office. And she convinced me that Tomi was right; I could do children's books." The relationship between Ursula Nordstrom and Shel Silverstein is mutually rewarding. He considers her a superb editor who knows when to leave an author-illlustrator alone. Asked if he would change something he had produced on an editor's say-so, he answered with a flat "No." But he added: "Oh, I will take a suggestion for revision. I do eliminate certain things when I'm writing for children if I think only an adult will get the idea. Then I drop it, or save it. But editors messing with content? No." Had he been surprised by the astronomical record of The Giving Tree, his biggest seller to date and one of the most successful children's books in years? Another emphatic no. "What I do is good," he said. "I wouldn't let it out if I didn't think it was." But The Giving Tree, which has been selling steadily since it appeared ten years ago and has been translated into French, is not his own favorite among his books. "I like Uncle Shelby's ABZ, A Giraffe and a Half and Lafcadio, the Lion Who Shot Back—I think I like that one the most."The Giving Tree is one of those rare creations that seem to defy categorization, appealing equally to the reverent and the irreverent, the sophisticated and the simple. It tells of a tree and the use a man makes of it. When he is a boy, he plays in the tree's branches and enjoys its luscious fruit. Later, he courts his love under the tree and uses some of its wood to build a house for his family. Years pass; the man is now old and alone. The tree lets him take its trunk to carve a boat from, and the man rows away. Finally he returns for the last time to sit and rest on the stump of the tree—all that's left of it.

Otto Penzler, in his crime anthology Murder for Revenge (1998), commented on Silverstein's versatility:

This anthology was the second in a series, which also included Murder for Love (1996) and Murder and Obsession (1999). All three anthologies included Silverstein contributions. He did not really care to conform to any sort of norm, but he did want to leave his mark for others to be inspired by, as he told Publishers Weekly:

I would hope that people, no matter what age, would find something to identify with in my books, pick up one and experience a personal sense of discovery. That's great. I think that if you're creative person, you should just go about your business, do your work and not care about how it's received. I never read reviews because if you believe the good ones you have to believe the bad ones too. Not that I don't care about success. I do, but only because it lets me do what I want. I was always prepared for success but that means that I have to be prepared for failure too. I have an ego, I have ideas, I want to be articulate, to communicate but in my own way. People who say they create only for themselves and don't care if they are published... I hate to hear talk like that. If it's good, it's too good not to share. That's the way I feel about my work. So I'll keep on communicating, but only my way. Lots of things I won't do. I won't go on television because who am I talking to? Johnny Carson? The camera? Twenty million people I can't see? Uh-uh. And I won't give any more interviews.

Silverstein's passion for music was clear early on as he studied briefly at Chicago College of Performing Arts at Roosevelt University. His musical output included a large catalog of songs; a number of which were hits for other artists, most notably the rock group Dr. Hook & The Medicine Show. He wrote Tompall Glaser's highest-charting solo single "Put Another Log on the Fire," "One's on the Way" (a hit for Loretta Lynn), "The Unicorn" (which became the signature piece for the Irish Rovers in 1968) and "25 Minutes to Go", sung by Johnny Cash, about a man on Death Row with each line counting down one minute closer. Silverstein also wrote one of Johnny Cash's best known whimsical hits, "A Boy Named Sue".

He wrote the lyrics and music for most of the Dr. Hook songs, including "The Cover of the Rolling Stone", "Freakin' at the Freakers' Ball," "Sylvia's Mother", "The Things I Didn't Say" and a cautionary song about venereal disease, "Don't Give a Dose to the One You Love Most". He wrote many of the songs performed by Bobby Bare, including "Rosalie's Good Eats Café", "The Mermaid", "The Winner" and "Tequila Sheila". He co-wrote with Baxter Taylor "Marie Laveau", for which the songwriters received a 1975 BMI Award. "The Mermaid" was covered in 2005 by Great Big Sea, which released its version on The Hard and the Easy album.

Silverstein's "The Ballad of Lucy Jordan", first recorded by Dr. Hook in 1975, was re-recorded by Marianne Faithfull (1979), Belinda Carlisle (1996), and Bobby Bare (2005) and later featured in the films Montenegro and Thelma & Louise. "Queen of the Silver Dollar" was first recorded by Dr. Hook on their 1972 album Sloppy Seconds, and later by Doyle Holly (on his 1973 album Doyle Holly), Emmylou Harris (on her 1975 album Pieces of the Sky), Barbie Benton (on her 1975 album Barbie Doll) and Dave & Sugar (on their 1976 album Dave & Sugar).

Silverstein composed original music for several films and displayed a musical versatility in these projects, playing guitar, piano, saxophone and trombone. He wrote "In the Hills of Shiloh", a poignant song about the aftermath of the Civil War, which was recorded by The New Christy Minstrels, Judy Collins, Bobby Bare and others. The soundtrack of the 1970 film Ned Kelly features Silverstein songs performed by Waylon Jennings, Kris Kristofferson and others.

Silverstein had a popular following on Dr. Demento's radio show. Among his best-known comedy songs were "Sarah Cynthia Sylvia Stout (Would Not Take The Garbage Out)", "The Smoke-Off" (a tale of a contest to determine who could roll...or smoke...marijuana joints faster), "I Got Stoned and I Missed It" and "Bury Me in My Shades". He wrote "The Father of a Boy Named Sue", in which he tells the story from the original song from the father's point of view, and the 1962 song "Boa Constrictor", sung by a man who is being swallowed by a snake (recorded by the folk group The Brothers Four), although it is now better known as a children's playground chant.

A longtime friend of American singer and songwriter Pat Dailey, Silverstein collaborated with him on the posthumously released 2002 Underwater Land album. It contains 17 children's songs written and produced by Silverstein and sung by Dailey. Silverstein also appears along with him on a few tracks. The album also contains artwork by Silverstein.

In 2010, Twistable, Turnable Man: A Musical Tribute to the Songs of Shel Silverstein was released on Sugar Hill Records. Artists covering Silverstein songs include Andrew Bird, My Morning Jacket, and Bobby Bare, Jr.

In January 1959, Look Charlie: A Short History of the Pratfall was a chaotic off-Broadway comedy staged by Silverstein, Jean Shepherd and Herb Gardner at New York's Orpheum Theatre on Second Avenue in the Lower East Side. Silverstein went on to write more than 100 one-act plays. The Devil and Billy Markham, published in Playboy in 1979, was later adapted into a solo one-act play that debuted on a double bill with Mamet's Bobby Gould in Hell (1989) with Dr. Hook vocalist Dennis Locorriere narrating. Karen Kohlhaas directed An Adult Evening of Shel Silverstein, produced by New York's Atlantic Theater Company in September 2001 with a variety of short sketches:

• "One Tennis Shoe" ... Harvey claims his wife is becoming a bag lady.
• "Bus Stop" ... Irwin stands on a corner with a "bust stop" sign.
• "Going Once" ... A woman auctions herself.
• "The Best Daddy" ... Lisa's daddy shot the pony he got for her birthday.
• "The Lifeboat is Sinking" ... Jen and Sherwin play a game of Who-Would-You-Save-If...the family was drowning.
• "Smile" ... Bender plans to punish the man responsible for the phrase "Have a nice day".
• "Watch and Dry" ... Marianne discovers her laundry hasn't been cleaned.
• "Thinking Up a New Name for the Act" ... Pete thinks "meat and potatoes" is the perfect name for a vaudeville act.
• "Buy One, Get One Free" ... Hookers offer a golden opportunity.
• "Blind Willie and the Talking Dog" ... Blind Willie's talking dog argues they could profit from his talent.

In December 2001, Shel's Shorts was produced in repertory as two separate evenings under the titles Signs of Trouble and Shel Shocked by the Market Theater in Cambridge, Massachusetts. Signs of Trouble was directed by Wesley Savick, and Shel Shocked was directed by Larry Coen.

Silverstein had two children. His first child was daughter Shoshanna (Shanna), born June 30, 1970, with Susan Hastings. Susan Hastings died five years later, on June 29, 1975, in Baltimore, Maryland. Shoshanna's aunt and uncle, Meg and Curtis Marshall, raised her from the age of five until her death of a cerebral aneurysm in Baltimore on April 24, 1982, at the age of 11. She was attending the Bryn Mawr School in Baltimore at the time of her death. Silverstein dedicated his 1983 reprint of Who Wants a Cheap Rhinoceros to the Marshalls. A Light in the Attic was dedicated to Shanna, and Silverstein drew the sign with a flower attached. Shoshanna means lily or rose in Hebrew. Silverstein's other child was his son Matthew, born in 1983. Silverstein's 1996 Falling Up was dedicated to Matt.

Later in life, Silverstein loved to spend time at his favorite places, such as Greenwich Village, Key West, Martha’s Vineyard and Sausalito, California. Silverstein continued to create plays, songs, poems, stories and drawings until his death in 1999. He died at his home in Key West, Florida on May 9, 1999, of a heart attack, and his body was found by two housekeepers the following Monday, May 10. It was reported that he could have died on either day that weekend.

Silverstein's "A Boy Named Sue" won a 1970 Grammy. He was nominated for an Oscar and a Golden Globe for his song "I'm Checkin' Out" in the film Postcards from the Edge. He was posthumously inducted into the Nashville Songwriters Hall of Fame in 2002.

• Take Ten (Pacific Stars and Stripes, 1955)
• Grab Your Socks! (Ballantine Books, 1956)
• Now Here's My Plan (Simon & Schuster, 1960) (First collection of American magazine cartoons)
• Uncle Shelby's ABZ Book (Simon & Schuster, 1961) (First book of original material for adults)
• Playboy's Teevee Jeebies (Playboy Press, 1963)
• The Lion Who Shot Back (Harper & Row, 1963) (First children's book)
• A Giraffe and a Half (HarperCollins, 1964)
• The Giving Tree (HarperCollins, 1964)
• Who Wants a Cheap Rhinoceros? (Macmillan, 1964)
• Don't Bump the Glump! and Other Fantasies (Simon and Schuster, 1964)
• More Playboy's Teevee Jeebies (Playboy Press, 1965)
• Where the Sidewalk Ends (HarperCollins, 1974) (First collection of poems)
• The Missing Piece (HarperCollins, 1976)
• Different Dances (HarperCollins, 1979)
• A Light in the Attic (HarperCollins, 1981)
• The Missing Piece Meets the Big O (HarperCollins, 1981)
• Falling Up (HarperCollins|1996)
• Draw a Skinny Elephant (HarperCollins, 1998)
• Runny Babbit (HarperCollins, 2005) (Published posthumously)
• Don't Bump the Glump! and Other Fantasies (HarperCollins, 2008 reissue)

Silverstein believed that written works needed to be read on paper...the correct paper for the particular work. He usually would not allow his poems and stories to be published unless he could choose the type, size, shape, color and quality of the paper. Being a book collector, he took seriously the feel of the paper, the look of the book, the fonts and the binding. Most of his books did not have paperback editions because he did not want his work to be diminished in any way.