As a poor student who excelled at running, Gregory was aided by teachers at Sumner High School such as Warren St. James. He earned a track scholarship to Southern Illinois University Carbondale . There he set school records as a half-miler and miler. His college career was interrupted for two years in 1954 when he was drafted into the U.S. Army. The army was where he got his start in comedy, entering and winning several Army talent shows at the urging of his commanding officer, who had taken notice of Gregory's penchant for joking. In 1956, Gregory briefly returned to the university after his discharge, but left without a degree because he felt that the university "didn't want me to study, they wanted me to run".

In the hopes of performing comedy professionally, he moved to Chicago, where he became part of a new generation of black comedians that included Nipsey Russell, Bill Cosby, and Godfrey Cambridge. These comedians broke with the minstrel tradition, which presented stereotypical black characters. Gregory drew on current events, especially the racial issues, for much of his material: "Segregation is not all bad. Have you ever heard of a collision where the people in the back of the bus got hurt?" .

Gregory met his wife Lillian at an African-American club; they married in 1959. They have ten children: Michele, Lynne, Pamela, Paula, Stephanie (aka Xenobia), Gregory, Christian, Miss, Ayanna and Yohance . The Gregorys had one child who died at birth.

In 1973 the Gregory family moved to Plymouth, Massachusetts, where he developed an interest in vegetarianism. In 1984 he founded Health Enterprises, Inc., a company that distributed weight loss products. In 1985 Gregory introduced the "Slim-Safe Bahamian Diet", a powdered diet mix. Economic losses caused in part by conflicts with his business partners led to his eviction from his home in 1992. Gregory remained active, however, and in 1996 returned to the stage in his critically acclaimed one-man show, "Dick Gregory Live!"

After completing military service, he performed as a comedian in small, primarily black nightclubs while working for the United States Postal Service during the daytime. In 1961, while working at the Black-owned Roberts Show Bar in Chicago, he was hired by Hugh Hefner to work at the Chicago Playboy Club after Hefner heard him perform the following material before a largely-white audience:

Good evening ladies and gentlemen. I understand there are a good many Southerners in the room tonight. I know the South very well. I spent twenty years there one night.

Last time I was down South I walked into this restaurant and this white waitress came up to me and said, "We don't serve colored people here." I said, "That's all right. I don't eat colored people. Bring me a whole fried chicken."

Then these three white boys came up to me and said, "Boy, we're giving you fair warning'. Anything you do to that chicken, we're gonna do to you". So I put down my knife and fork, I picked up that chicken and I kissed it. Then I said, "Line up, boys!" . This routine caused a direct request from publisher Hugh Hefner and he was booked as a replacement for the white comedian Professor Irwin Corey. Until then Gregory had worked mostly at small clubs with predominantly black audiences.

Active in the civil rights movement, he came to Selma, Alabama and spoke for two hours on a public platform two days before the voter registration drive known as "Freedom Day" (October 7, 1963) .

Dick Gregory's first TV appearance was on the late night Jack Paar Show. He soon began appearing nationally and on television and his 1964 autobiography, nigger, has sold ten million copies. At the same time, he became more involved in struggles for civil rights, activism against the Vietnam War, economic reform, anti-drug issues, conspiracy theories, and others. As a part of his activism, he went on several hunger strikes. Gregory began his political career by running against Richard J. Daley for the mayoralty of Chicago in 1967. Though he did not emerge victorious, this would not prove to be the end of Dick Gregory's dalliances with electoral politics.

Gregory unsuccessfully ran for President of the United States in 1968 as a write-in candidate of the Freedom and Peace Party, which had broken off from the Peace and Freedom Party. He won 47,097 votes (including one from Hunter S. Thompson) with fellow activist Mark Lane as his running mate in some states, David Frost in others, and Dr. Benjamin Spock in Virginia and Pennsylvania garnering more than the party he had left . The Freedom and Peace Party also ran other candidates, including Beulah Sanders for New York State Senate and Flora Brown for New York State Assembly . His efforts landed him on the master list of Nixon political opponents.

He then wrote the book Write Me In about his presidential campaign. One interesting anecdote in the book related the story of a publicity stunt which came out of Operation Breadbasket in Chicago where the campaign had printed $1 bills with Gregory's image on them. Some of these bills made it into circulation in cash transactions causing considerable problems, but priceless publicity.

The majority of these bills were quickly seized by the federal government. A large contributing factor to the seizure came from the bills resembling authentic US currency enough that they worked in many dollar cashing machines of the time. Gregory avoided being charged with a federal crime, later joking that the bills couldn’t really be considered US currency because "everyone knows a black man will never be on a US bill."

Shortly after this time Mr. Gregory became an outspoken critic of the Warren Commission findings that President JFK was assassinated by Lee Harvey Oswald. On March 6, 1975 Mr. Gregory and assassination researcher Robert Groden appeared on Geraldo Rivera's late night ABC talk show Goodnight America. An important historical event happened that night when the famous Zapruder film of JFK's assassination was shown to the public on TV for the first time in history. The public's response and outrage to that showing led to the forming of the Hart-Schweiker investigation, which contributed to the Church Committee Investigation on Intelligence Activities by the United States, which resulted in the House Select Committee on Assassinations investigation.

Gregory was an outspoken feminist activist, and in 1978 he joined Gloria Steinem, Betty Friedan, Bella Abzug, Margaret Heckler, Barbara Mikulski, and original suffragists to lead the National ERA March for Ratification and Extension, a march down Pennsylvania Avenue to the United States Capitol of over 100,000 on Women's Equality Day (August 26), 1978 to demonstrate for a ratification deadline extension for the proposed Equal Rights Amendment to the United States Constitution, and for the ratification of the ERA. The march was ultimately successful in extending the deadline to June 30, 1982, and Gregory joined other activists the Senate for celebration and victory speeches by pro-ERA Senators, Congressmen, Congresswomen, and activists. The ERA still narrowly failed to be ratified by the extended ratification date, however, but the Women's Movement was largely successful in securing gender equality in the laws and society.

On July 21, 1979, Gregory appeared at the Amandla Festival where Bob Marley, Patti LaBelle and Eddie Palmieri, amongst others, had performed. Gregory held a speech before Marley's performance, blaming President Carter, and showing his support for the international Anti-Apartheid movements. Gregory and Mark Lane did landmark research into the assassination of Dr. Martin Luther King, Jr., which helped move the U.S. House Assassinations Committee to investigate the murder, along with that of John F. Kennedy. Lane was author of conspiracy theory books such as Rush to Judgment. The pair wrote the MLK conspiracy book Code Name Zorro, which postulated that convicted assassin James Earl Ray did not act alone. Gregory has also argued that the moon landing was faked and the commonly accepted account of the 9/11 attacks is wrong, among other conspiracy theories.

Gregory was an outspoken activist during the US Embassy Hostage Crisis in Iran. In 1980 he traveled to Tehran to attempt to negotiate the hostages' release and engaged in a public hunger strike there, weighing less than 100 pounds (45 kg) when he returned to the United States.

In 1998 Gregory spoke at the celebration of the birthday of Dr. Martin Luther King, Jr. and President Clinton was in attendance. Not long after that, the President told Gregory’s long-time friend and P.R. Consultant, Steve Jaffe, “I love Dick Gregory, he is one of the funniest people on the planet.” They spoke of how Gregory had made a comment on Dr. King’s birthday that broke everyone into laughter, when he noted that the President made Speaker Newt Gingrich ride “in the back of the plane,” on an Air Force One trip overseas.

According to a June 2000 JET Magazine interview, Gregory stated that he was diagnosed with lymphoma in late 1999. Gregory reported that he was treating the cancer with herbs, vitamins and exercise which he believes has kept the cancer in remission .

Since the late 1980s, Gregory has been a figure in the health food industry by advocating for a raw fruit and vegetable diet. Gregory first became a vegetarian in the 1960s, and has lost a considerable amount of weight by going on extreme fasts, some lasting upwards of 50 days. He developed a diet drink called "Bahamian Diet Nutritional Drink" and went on TV shows advocating for his diet and to help the morbidly obese. He is probably best remembered for his attempts, chronicled in the media on daytime talk shows in early 1988, at helping 1,200 pound (540 kg) Long Island man Walter Hudson drop nearly 600 pounds (270 kg) in only a few months on a liquid diet .

At a Civil Rights rally marking the 40th anniversary of the Voting Rights Act, Gregory criticized the United States, calling it "the most dishonest, ungodly, unspiritual nation that ever existed in the history of the planet. As we talk now, America is 5 percent of the world's population and consumes 96 percent of the world's hard drugs".

Gregory announced a hunger strike on Sept. 10, 2010, saying in a commentary published by the Centre for Research on Globalisation in Montreal that he doubted the official U.S. report about the attacks on Sept. 11, 2001. "One thing I know is that the official government story of those events, as well as what took place that day at the Pentagon, is just that, a story. This story is not the truth, but far from it. I was born on October 12, 1932. I am announcing today that I will be consuming only liquids beginning Sunday until my eightieth birthday in 2012 and until the real truth of what truly happened on that day emerges and is publicly known."

He is number 81 on Comedy Central's list of the 100 Greatest Standups of all time and has his own star on the St. Louis Walk of Fame. There is a grassroots effort afoot to get him a star on the Hollywood Walk of Fame, spearheaded by Radio One host Joe Madison.

Gregory is a member of Alpha Phi Alpha, the first intercollegiate Greek-letter fraternity established for African Americans.

Gregory was a former co-host with radio personality Cathy Hughes, and is still a frequent morning guest, on WOL 1450 AM talk radio's "The Power", the flagship station of Hughes' Radio One. He also appears regularly on the nationally syndicated Imus in the Morning program.

Gregory appears as "Mr. Sun" on the television show Wonder Showzen (the third episode, titled "Ocean", aired in 2005). As Chauncey, a puppet character, imbibes a hallucinogenic substance, Mr. Sun warns, "Don't get hooked on imagination, Chauncey. It can lead to terrible, horrible things." Gregory also provides guest commentary on the Wonder Showzen Season One DVD. Large segments of his commentary were intentionally bleeped out, including the names of several dairy companies, as he made potentially slanderous remarks concerning ill effects that the consumption of cow milk may have on human beings.

Gregory attended and spoke at the funeral of James Brown on December 30, 2006, in Augusta, Georgia.

Dick Gregory is occasionally a guest on the Mark Thompson's "Make It Plain" Sirius Channel 146 Radio Show from 3pm to 6pm PST.

Mr. Gregory appeared on The Alex Jones Show on September 14th, 2010.