In 1958, at LeMoyne-Owens, he criticized a college trustee for remarks he felt were demeaning to African Americans, which nearly caused his expulsion. While a senior and the President of the NAACP chapter, Barry heard of Walter Chandler—the only white member on LeMoyne-Owen's board of trustees—making comments that black people should be treated as a "younger brother not as an adult". Barry wrote a letter to LeMoyne's President objecting to the comments and asking if Walter Chandler could be removed from the board. A friend of Barry's was the Editor of the school newspaper, the Magician, and told Barry to run the letter in the paper. From there, the letter made it to the front page of Memphis’ conservative morning paper.

In 1960, Barry was elected as the first chairman of the Student Nonviolent Coordinating Committee (SNCC). He helped develop an organizing project in McComb, Mississippi. The project was both a voter registration and a direct action endeavor. Barry said he and other Activists lived with the local people in order to stay safe, as well as to learn what it was like to live there. They could use that information to organize the members of the SNCC accordingly.

As head of SNCC, Barry led protests against racial segregation and discrimination. After he left McComb, Barry's lobbied the state legislatures to try to convince them to vote to make the Mississippi Freedom Democratic Party (MFDP) the recognized Democratic party of Mississippi in the 1964 Democratic National Convention. In a protest of their continuing disenfranchisement, African Americans had organized this party to prove that blacks wanted to vote and conducted a trial election. Barry slept on the boardwalk in Atlantic City the night after speaking to the New Jersey Legislature.

In 1965, Barry and Evans moved to Washington, D.C., to open a local chapter of SNCC. He was deeply involved in coordinating peaceful street demonstrations as well as a boycott to protest bus fare increases. Barry organized rides to work for those who needed them. The boycott cost the bus line thousands of dollars, and Barry proved his ability to organize.

He also served as the leader of the Free D.C. Movement, strongly supporting increased home rule, as a Congressional committee exercised administrative rule over the district. Barry quit SNCC in 1967, when H. Rap Brown became chairman of the group. In 1967, Barry and Mary Treadwell co-founded Pride, Inc., a Department of Labor-funded program to provide job training to unemployed black men. The group employed hundreds of teenagers to clean littered streets and alleys in the district. Barry and Treadwell had met while students at Fisk University, and they later met again while picketing in front of the Washington Gas Light Company.

Barry was active in the aftermath of the 1968 Washington, D.C. riots that followed the assassination of Martin Luther King, Jr. in Memphis. He organized through Pride Inc. a program of free food distribution for poor black residents whose homes and neighborhoods had been destroyed in the rioting. Barry convinced the Giant Food supermarket chain to donate food, and he spent a week driving trucks and delivering food throughout the city's housing projects. He also became a board member of the city's Economic Development Committee, helping to route federal funds and venture capital to black-owned businesses that were struggling to recover from the riots.

When President Richard Nixon declared July 21, 1969, National Day of Participation in honor of the moon landing by Apollo 11, Barry criticized him. Barry believed that Dr. Martin Luther King, Jr. deserved a national honor day on his birthday, which Nixon had opposed. Said Barry, "Why should blacks feel elated when we see men eating on the moon when millions of blacks and poor whites don't have enough money to buy food here on earth?"

In 1971, Barry announced his candidacy for at-large member of the school board, running against the incumbent, Anita L. Allen. Barry said he wanted to steer the school board back to the "issues of education" and away from problems of personalities. Barry defeated Allen, with 58 percent of the vote to Allen's 34 percent.

In response to the 1972 blaxploitation film Super Fly, Barry quickly formed a protest group named Blacks Against Narcotics and Genocide (BANG). Barry said the film was harmful to black youth, and that it glorified drug abuse. BANG called for a boycott of the film.

Upon establishment of Washington's home rule in 1974, Barry was elected an at-large member of Washington's first elected city council. In that position, he served as chair of the District of Columbia Committee on Finance and Revenue. He was re-elected in 1976.

While serving on the D.C. City Council, Barry was shot on March 9, 1977, by radical Hanafi Muslims (from a breakaway sect of the Nation of Islam) when they overran the District Building. Barry was shot near his heart during the two-day 1977 Hanafi Siege in which hostages were held by the terrorists. This was finally defused by the FBI and Muslim ambassadors. Barry recovered from his injury.

Having credentials as an Activist, legislator, and "hero" in a hostage crisis, as well as an early endorsement from the Washington Post, Barry was elected as mayor after Walter Washington, the district's first mayor, fell out of political favor in the 1978 election.

However, unemployment rose dramatically during Barry's first administration, as did crime rates, in part because many of his layoffs were centered in the police department (1,500 terminations by 1981). His campaign promise to "take the boards off" public housing – i.e., to rehabilitate dilapidated and condemned public housing units – was slow in fulfillment. The city's debt was a constant Problem as well: Barry had recalculated the Washington Administration's claim of a $41 million surplus and found that the city was $285 million in debt, a long-term accrual that his annual surpluses were unable to surmount by the end of his term. Graft and embezzlement among Barry appointees, such as Employment Services Director Ivanhoe Donaldson, began late in Barry's first term, although it would not be discovered for several years. Barry was personally touched by a number of "mini-scandals". He had travels with finances he often kept secret. He was first reported to be using cocaine at downtown nightclubs.

In 1982, Barry faced re-election against a challenge from fellow Democrat Patricia Roberts Harris, an African-American woman who had served in two cabinet positions under President Jimmy Carter, as well as from council members John L. Ray and Charlene Drew Jarvis. In the primary election held September 14, 1982, Barry won by a landslide, with over 58% of the vote. He won 82% of the vote in the November 11 general election against Republican candidate E. Brooke Lee.

Major scandal caught up to the mayor in his second term. Several of his associates were indicted for financial malfeasance, including former administration officials Ivanhoe Donaldson and Alphonse G. Hill. Barry began to be plagued by rumors and press reports of womanizing and of alcohol and drug abuse; in particular, stories abounded of his cocaine use in the city's nightclubs and red-light district. In 1983, Barry's ex-wife, Mary Treadwell, was convicted of fraudulently using federal funds given to Pride, Inc., a group that helped local youth find employment. In 1984, Barry's one-time lover Karen Johnson was convicted of cocaine possession and contempt of court for refusing to testify to a grand jury about Barry's drug use. Barry's second four years in office had some high points, including the District's entry into the open bond market with Wall Street's highest credit rating, and Barry's nomination speech for Jesse Jackson at the 1984 Democratic Convention.

Barry came to national prominence as mayor of the national capital, the first prominent civil rights Activist to become chief executive of a major American city. He gave the presidential nomination speech for Jesse Jackson at the 1984 Democratic National Convention. His Celebrity was transformed into international notoriety in January 1990, when he was videotaped during a sting operation smoking crack cocaine and was arrested by Federal Bureau of Investigation (FBI) officials on drug charges. The arrest and subsequent trial precluded Barry seeking re-election, and he served six months in a federal prison. After his release, he was elected to the Council of the District of Columbia in 1992. He was elected again as mayor in 1994, serving from 1995 to 1999.

Barry sought a third term as mayor in 1986. By this time, his dominance of city politics was so absolute that he faced only token opposition in the Democratic primary in the form of former school board member Mattie Taylor, whom Barry dispatched rather easily. Barry had expected to face Jesse Jackson, who had been encouraged by colleagues to seek the mayoralty, and who had been relatively popular in stark contrast to Barry's declining reputation. Barry, who knew that most of Jackson's income came from delivering speeches, used his political clout to arbitrarily disqualify Jackson by getting a law passed that said anyone who made more than a certain amount in honoraria was ineligible to run for D.C. office. Council members jokingly called this the "Jesse Jackson law," as it was legislated expressly to keep Jackson out of the mayoral race. As expected, Barry defeated Republican city councilwoman Carol Schwartz fairly handily in the November 4 general election. However, Schwartz managed to win 33 percent of the vote—the first time a Republican had crossed the 30-percent barrier in a general election. For the third time, Barry received the endorsement of The Washington Post but "with far greater reservations and misgivings" than at any time in the past.

In 1987 crack use exploded in the city, as did territorial wars among drug dealers; in 1988 there were 369 homicides in Washington, D.C., the most ever in the city. That record was broken when the next year had 434 homicides, and it was broken again in 1990 with 474 homicides, making Washington's murder rate the highest in the nation. The Washington, D.C. government's employment and deficits grew as city services suffered; in particular, there were frequent press reports of deaths occurring because police lacked cars to get to crime scenes, and EMS services responded slowly or went to the wrong address.

By late 1989, federal officials had been investigating Barry on suspicion of illegal drug possession and use; that fall, they prosecuted several of Barry's associates for cocaine use, including Charles Lewis, a native of the United States Virgin Islands. He was implicated in a drug investigation involving Barry and a room at Washington's Ramada Inn in December 1988.

As a result of his arrest and the ensuing trial, Barry decided in June 1990 not to seek re-election as mayor. After his arrest and through his trial, Barry continued as mayor. He even ran as an independent for an at-large seat on the council against 74-year-old incumbent Hilda Mason. Mason, a former ally who had helped Barry recuperate after the 1977 shooting, took the challenge personally, saying, "I do feel very disappointed in my grandson Marion Barry." Mason was endorsed by a majority of the council members and by Jesse Jackson, who was running for Shadow senator.

Barry was released from prison in 1992, and two months later filed papers to run for the Ward 8 city council seat in that year's election. Barry ran under the slogan "He May Not Be Perfect, But He's Perfect for D.C." He defeated the four-term incumbent, Wilhelmina Rolark, in the Democratic primary, winning 70 percent of the vote, saying he was "not interested in being mayor", and went on to win the general election easily.

Barry married Cora Masters on January 8, 1993. Masters was a political science professor at the University of the District of Columbia and his former spokeswoman. Barry's mother, Mattie Cummings, died at age 92 in Memphis on November 8, 2009.

Despite his earlier statements to the contrary, observers of Barry's council victory expressed beliefs that he was laying ground for a mayoral run in 1994. Indeed, Barry fulfilled expectations when he formally announced his candidacy for mayor on May 21, 1994, and was immediately regarded as a serious challenge to the unpopular incumbent mayor, Sharon Pratt Kelly. Despite much opposition, including an abortive effort to recall his 1992 council election, Barry won a three-way Democratic primary contest for mayor with 48% of the vote on September 13, pushing Kelly into last place. The victory, coming after Barry's videotaped crack use and conviction, shocked the nation, carrying front-page headlines in newspapers such as the Los Angeles Times and Boston Globe.

Barry was sworn into office on January 2, 1995, and was almost immediately confronted with a financial crisis. The budgetary problems of his previous administrations had only increased during Kelly's term, with city officials estimating a fiscal 1996 deficit between $700 million and $1 billion. In addition, city services remained extremely dysfunctional due to mismanagement. One month into his term, Barry declared that the city government was "unworkable" in its present state and lobbied Congress to take over the areas of its operation that were analogous to typical state government functions. Wall Street, which Barry had convinced just after his election to continue investing in municipal bonds, reduced the city's credit rating to "junk status." Instead of implementing Barry's proposals, the newly Republican Congress (who had come to power on promises of decreasing federal spending) placed several city operations into receivership and created the District of Columbia Financial Control Board to assume complete authority over the city's day-to-day spending and finances, including overrule of the mayor's fiscal decisions.

Barry declined to run for a fifth term in office in June 1998, stating his belief that Congress would not restore full home rule while he was mayor. He was succeeded by city CFO Anthony A. Williams.

After leaving office, Barry performed consulting work for an investment banking firm. On March 6, 2002, Barry declared his intention to challenge at-large council member Phil Mendelson in the Democratic primary. Within a month, he decided against running, after an incident in which U.S. Park Police found traces of marijuana and cocaine in his car.

On June 12, 2004, Barry announced that he was running in the Democratic primary for the Ward 8 council seat, a position he held before becoming mayor. Barry received 58% of the vote, defeating the incumbent council member, Sandy Allen, on September 14, 2004. Barry received 95% of the vote in the general election, giving him a victory in the race to represent Ward 8 in the Council.

On October 28, 2005, Barry pleaded guilty to the misdemeanor charges stemming from an IRS investigation. The mandatory drug testing for the hearing showed Barry as being positive for cocaine and marijuana. On March 9, 2006, he was sentenced to three years probation for misdemeanor charges of failing to pay federal and local taxes, and underwent drug counseling.

On December 16, 2006, the Park Police pulled over Barry for driving too slowly, which Barry later said was because he was trying to figure out where to enter an elementary school's parking lot for a nonprofit foundation's event. After looking up Barry's record, the police officer told Barry that his license had been suspended and ticketed Barry for operating a vehicle on a suspended license, despite Barry's insistence to the contrary. Two days later, the D.C. Department of Motor Vehicles confirmed that Barry's license had not actually been suspended and said a computer glitch must have caused the error.

In 2007, federal prosecutors sought to have his probation revoked for failure to file his 2005 tax return. U.S. Magistrate Judge Deborah Robinson refused, saying that prosecutors had not proved that the failure was willful, even if Barry was aware he had missed the deadline. According to Judge Robinson, sentencing Barry to jail without proving that he willfully failed to file his taxes would contradict precedent set by the United States Supreme Court.

Barry ran for re-election in 2008 and easily held off all five challengers in the Democratic primary: Ahmad Braxton-Jones, Howard Brown, Chanda McMahan, Sandra Seegars and Charles Wilson. No Republican or Statehood Green candidates filed to run in the Ward 8 council race.

An investigative report by a special counsel said that Barry had personally benefited from a contract that he had awarded to his then-girlfriend Donna Watts-Brighthaupt. The report stated that Barry had awarded a contract to Watts-Brighthaupt, who then repaid money owed to Barry with the proceeds of the contract. When interviewed by the special counsel, Watts-Brighthaupt admitted to plagiarizing substantial portions of her study from a publicly available study by the United States Department of Education. The special counsel report also said that Barry had requested 41 earmarks in 2009 worth $8.4 million, some of which were paid to organizations "rife with waste and abuse." The report also said that Barry had impeded the investigation by refusing to respond to questions and by telling witnesses not to respond to questions and not give subpoenaed documents to the special counsel.

In response to the special counsel's report, several council members said they would like to hear a response from Barry before considering a censure. On March 2, 2010, the Council of the District of Columbia voted 12–0 in favor of stripping Barry of all committee assignments, ending his chair of the Committee on Housing and Workforce Development, and removing him from the Committee on Finance and Revenue.

On September 9, 2011, the Internal Revenue Service filed a notice of federal tax lien against Barry because of $3,200 of unpaid federal income taxes for 2010. Barry attributed the lien to poor communication between the Internal Revenue Service and his representatives.

At a party celebrating his primary victory for his D.C. council seat on April 3, 2012, Barry said, "We've got to do something about these Asians coming in, opening up businesses, those dirty shops. They ought to go, I'll just say that right now, you know. But we need African-American Business People to be able to take their places, too."

In May 2013, after Toronto mayor Rob Ford was allegedly videotaped smoking what was reported to be crack, parallels were made with the similarity to the 1990 incident. Barry denied any similarity, stating: "Unless he was entrapped by the government, it's not similar."

In the midst of a contentious mayoral race in Newark, New Jersey in May 2014, Rutgers University professor and Newark city Historian Clement A. Price cited Barry and Jackson, Mississippi's Chokwe Lumumba as his role Models as mayor. The citation came in an April 2014 public discussion. Professor Price had not taken sides in the 2014 contest. In June 2009, a documentary of Barry's life was released at Silverdocs. The HBO Documentary was released on August 2009, on HBO.

Barry married Effi Slaughter, his third wife, just after announcing his candidacy for mayor in 1978. The couple had one son, Marion Christopher Barry, who died of a drug overdose on August 14, 2016. The Barrys separated in November 1990, soon after he was caught on videotape smoking crack cocaine with an ex-model and propositioning her for sex. They divorced in 1993, but she returned to Washington and supported him in his successful bid for a city council seat in 2004. Effi died on September 6, 2007, after an 18-month battle with acute myeloid leukemia.