Grizzard was born in Fort Benning, Georgia. His father, Lewis Grizzard, Sr., a soldier in the United States Army, left his mother Christine, a school teacher, when Lewis was young, and the mother and son moved in with Christine's parents in Moreland, Georgia, where Lewis would spend the rest of his childhood. Grizzard would recount his often frustrating relationship with his father in My Daddy Was a Pistol and I'm a Son of a Gun. He began his writing early, publishing stories of his little league team in the nearby Newnan Times-Herald, Newnan, Georgia.

Grizzard attended the University of Georgia in Athens, Georgia where he was a member of the Sigma Pi Fraternity and Gridiron Secret Society. During his time in Athens he became an avid Georgia Bulldogs fan. He studied journalism, but he shunned the school newspaper in favor of the independent Athens Daily News. After graduating with a B.A. in journalism in 1968, Grizzard moved on to Atlanta, joining the Atlanta Journal, and becoming the youngest ever executive sports editor of the Journal at the age of 23. The Executive Editor of the Journal, Jim Minter, said that had Grizzard stayed there, he would be remembered today as one of the great newspaper editors of the 20th century. His time there included the Marshall University football team tragedy and the Journal's coverage of Hank Aaron's 715th home run.

Grizzard then left to become the executive sports editor at the Chicago Sun-Times. He would later recall this as the most miserable period of his life. His tenure included a controversy involving the removal of several news columns written by Lacey Banks, the Sun-Times' first African-American sports columnist, from the newspaper, which resulted in Banks charging racism against Grizzard and led to Banks's subsequent firing. Although the newspaper, under editor Jim Hoge, supported Grizzard, a federal arbitrator reinstated Banks, and he criticized Grizzard as "racially insensitive". Grizzard, for his part, contended that the arbitrator did not understand the newspaper business, and he pointed out that he had replaced Banks with Thom Greer, a writer who was also African-American. Grizzard felt this invalidated any charge of racism. One Chicago radio announcer who sympathized with Grizzard said that Grizzard had been pronounced "guilty by geography". Grizzard was also divorced for the second time while living in Chicago. Grizzard's career as a newspaper man in Chicago is recalled in If I Ever Get Back to Georgia, I'm Gonna Nail My Feet to the Ground.

In 1977, Grizzard returned to Atlanta as a columnist for the sports section of the Atlanta Constitution newspaper. After eight months, he switched to writing the humor/life column that would eventually make him famous. He published this column about four days per week. At his peak, he was syndicated in 450 newspapers and making regular appearances on television and the stand-up comedy circuit. His popularity in Atlanta was such that the alternative newspaper Creative Loafing, in its annual "Best of Atlanta" poll, included the categories "Best Columnist" and "Best Columnist besides Lewis Grizzard".

Grizzard often drew criticism for his disparaging remarks about gay people and feminists, and his dislike for the New South and reflections on the "Old South" just of his youth were frequently misinterpreted. Nevertheless, he was extremely popular in the South, and he had enduring popularity across the nation because of the perceived humor, humanity, patriotism, and "old-fashioned" values that permeated his writing. His frequent bewilderment by sociocultural trends in the 1980s and 1990s struck a chord with many Baby Boom readers. Grizzard refused to use computers, writing every column or book on a regular typewriter. ("When I write, I like to hear some noise", he said.)

In 1988, Grizzard made his acting debut on the sitcom Designing Women, in the episode "Oh Brother", which first aired on 18 January 1988. Grizzard played the role of Clayton Sugarbaker, the half-brother of Julia and Suzanne Sugarbaker. Clayton was a former mental patient aspiring to be a stand-up comedian.

Grizzard had a somewhat troubled life, battling alcoholism, and going through three divorces. He was voted "The Author From Hell" at a publishing convention for his behavior on book tours. He also suffered from a congenital heart defect - a valve problem. In his own words, "There are three little leaflets that control the flow of blood to the heart. I was born with only two of those leaflets. It was just after the Great War, so there may have been a shortage. Either that or my daddy didn't get a good toe-hold." His near-death after his third valve-replacement surgery in 1993 brought in over 50,000 letters from well-wishers. He later attributed his miraculous recovery to the prayers of his fans.

Some time after marrying for the fourth time, Grizzard died of complications of his fourth heart-valve surgery. Grizzard suffered from brain damage, according to one report, from lack of oxygen to his brain. Had he survived, he would have been quite impaired. In accordance with his wishes, his body was cremated, and some of his ashes were scattered at the 50-yard line of the Sanford Stadium at the University of Georgia. The typewriter he used to author columns about the Atlanta Braves 1991 "worst to first" season is on display in the library of the University of Georgia's Grady College of Journalism and Mass Communication.

Grizzard never fathered any children, but he did adopt the daughter of his fourth wife.

• Kathy Sue Loudermilk, I Love You: A Good Beer Joint Is Hard to Find and Other Facts of Life (1 December 1979) (Collection of previously published Atlanta Journal-Constitution columns)
• Won't You Come Home, Billy Bob Bailey?: An Assortment of Home-Cooked Journalism for People Who Wonder Why Clean Underwear Doesn't Grow on Trees (1 November 1980) (Collection of previously published Atlanta Journal-Constitution columns)
• Glory! Glory! Georgia's 1980 Championship Season: The Inside Story (1981) (Loran Smith with Lewis Grizzard)
• Don't Sit Under The Grits Tree With Anyone Else But Me (1 November 1981) (Collection of previously published Atlanta Journal-Constitution columns)
• They Tore Out My Heart and Stomped That Sucker Flat (1 October 1982)
• If Love Were Oil, I'd Be About A Quart Low (1 October 1983)
• Elvis Is Dead and I Don't Feel So Good Myself (1 October 1984)
• Shoot Low Boys - They're Riding Shetland Ponies (1 October 1985)
• My Daddy Was A Pistol and I'm a Son of a Gun (1 October 1986)
• When My Love Returns From The Ladies Room, Will I Be Too Old To Care? (1 October 1987) (Collection of previously published Atlanta Journal-Constitution columns)
• Don't Bend Over In the Garden, Granny - You Know Them Taters Got Eyes (1 October 1988)
• Lewis Grizzard on Fear of Flying (1 April 1989)
• Lewis Grizzard's Advice To The Newly Wed . . . & the Newly Divorced (1 April 1989)
• Chili Dawgs Always Bark At Night (1 September 1989) (Collection of previously published Atlanta Journal-Constitution columns)
• Does A Wild Bear Chip In The Woods? (1 May 1990)
• If I Ever Get Back To Georgia, I'm Gonna Nail My Feet To The Ground (1 October 1990)
• Don't Forget To Call Your Momma; I Wish I Could Call Mine (1 April 1991)
• You Can't Put No Boogie Woogie On The King of Rock and Roll (1 October 1991) (Collection of previously published Atlanta Journal-Constitution columns)
• I Haven't Understood Anything Since 1962 and Other Nekkid Truths (1 October 1992)
• I Took A Lickin' and Kept on Tickin' and Now I Believe In Miracles (1 January 1994)

Posthumous collections

• The Last Bus To Albuquerque (1 September 1994) (Collection of previously published Atlanta Journal-Constitution columns)
• It Wasn't Always Easy But I Sure Had Fun (1 November 1994) (Collection of previously published material)
• Life Is Like a Dogsled Team . . . : If You're Not the Lead Dog, the Scenery Never Changes...The Wit and Wisdom of Lewis Grizzard (1 May 1995) (Collection of previously published material)
• Grizzardisms: The Wit and Wisdom of Lewis Grizzard (1 June 1995) (Collection of previously published material)
• Southern By The Grace of God - Lewis Grizzard on the South (1 May 1996) (Collection of previously published material)

• Chuck Perry. Don't Fence Me in: An Anecdotal Biography of Lewis Grizzard. 1995.

"Sportin' Life of Lewis Grizzard", a biography by Frank Hyland.2009