Lewis represents Georgia's 5th congressional district, one of the most consistently Democratic districts in the nation. Since its formalization in 1845, the district has been represented by a Democrat for all but eleven years.

In an interview with CNN during the 40th anniversary of the Freedom Rides, Lewis recounted the sheer amount of violence he and the 12 other original Freedom Riders endured. In Anniston, Alabama, the bus was fire-bombed after Ku Klux Klan members deflated its tires, forcing it to come to a stop. Lewis, however, was not present on that particular day. In Birmingham, the Riders were mercilessly beaten, and in Montgomery, an angry mob met the bus, and Lewis was hit in the head with a wooden crate. "It was very violent. I thought I was going to die. I was left lying at the Greyhound bus station in Montgomery unconscious," said Lewis, remembering the incident.

After nine years as a member of the U.S. House of Representatives, Fowler gave up the seat to make a successful run for the U.S. Senate. Lewis decided to run for the 5th district again. In the August Democratic primary, where a victory was considered tantamount to election, State Representative Julian Bond ranked first with 47%, just three points shy of winning outright. Lewis earned 35% in second place. In the run-off, Lewis pulled an upset against Bond, defeating him 52% to 48%. The race was said to have "badly strained relations in Atlanta's black community". Lewis was "endorsed by the Atlanta newspapers and a favorite of the white liberal establishment", with his victory coming from his strong polling among white voters (a minority in the district). During the campaign, he ran advertisements accusing Bond of corruption, implying that Bond used cocaine, and suggesting that Bond had lied about his civil rights activism.

In an interview for the Grio, on the 50th anniversary of the March on Washington, Lewis told a reporter, "We have not yet created a truly multiracial democratic society in America. It's not post-racial." On an African American being elected President, he said:

The Nashville sit-in movement was responsible for the desegregation of lunch counters in downtown Nashville. Lewis was arrested and jailed many times in the nonviolent movement to desegregate the downtown area of the city. Afterwards, he participated in the Freedom Rides sponsored by the Congress of Racial Equality (CORE), led by James Farmer, and ultimately became a national leader in the movement for civil rights and respect for human dignity. In an interview, John Lewis said, "I saw racial discrimination as a young child. I saw those signs that said 'White Men, Colored Men, White Women, Colored Women'. ... I remember as a young child with some of my brothers and sisters and first cousins going down to the public library trying to get library cards, trying to check some books out, and we were told by the librarian that the library was for whites only and not for 'coloreds'." During a childhood trip to Buffalo, New York, Lewis saw for the first time black men and white men working together, desegregating water fountains, and began to believe the dream of equality was more than just a dream. Lewis listened to Dr. Martin Luther King, Jr. and Rosa Parks on the radio, and he and his family supported the Montgomery Bus Boycott. Lewis met Parks in 1957 when he was 17, and he met King the following year.

In 1960, Lewis became one of the 13 original Freedom Riders. There were seven whites and six blacks who were determined to ride from Washington, D.C., to New Orleans in an integrated fashion. At that time, several states of the old Confederacy still enforced laws prohibiting black and white riders from sitting next to each other on public transportation. The Freedom Ride, originated by the Fellowship of Reconciliation and revived by James Farmer and CORE, was initiated to pressure the federal government to enforce the Supreme Court decision in Boynton v. Virginia (1960) that declared segregated interstate bus travel to be unconstitutional. In the South, Lewis and other nonviolent Freedom Riders were beaten by angry mobs, arrested at times and taken to jail. When CORE gave up on the Freedom Ride because of the violence, Lewis and fellow Activist Diane Nash arranged for the Nashville students to take it over and bring it to a successful conclusion.

In 1963, as chairman of SNCC Lewis was named one of the "Big Six" Leaders who were organizing the March on Washington, the occasion of Dr. King's celebrated "I Have a Dream" speech, along with Whitney Young, A. Philip Randolph, James Farmer and Roy Wilkins. Lewis also spoke at the March. Discussing the occasion, Historian Howard Zinn wrote: "At the great Washington March of 1963, the chairman of the Student Nonviolent Coordinating Committee (SNCC), John Lewis, speaking to the same enormous crowd that heard Martin Luther King's I Have a Dream speech, was prepared to ask the right question: 'Which side is the federal government on?' That sentence was eliminated from his speech by organizers of the March to avoid offending the Kennedy Administration. But Lewis and his fellow SNCC workers had experienced, again and again, the strange passivity of the national government in the face of Southern violence." At 23 he was the youngest speaker that day and is the last remaining living speaker.

Lewis draws on his historical involvement in the Civil Rights Movement as part of his politics. He "makes an annual pilgrimage to Alabama to retrace the route he marched in 1965 from Selma to Montgomery – a route Lewis has since had declared part of the Historic National Trails program. That trip has become one of the hottest tickets in Washington among lawmakers, Republican and Democrat, eager to associate themselves with Lewis and the movement. 'We don't deliberately set out to win votes, but it's very helpful,' Lewis said of the trip.". In recent years, however, Faith and Politics Institute has drawn criticism for selling seats on the trip to lobbyists for at least $25,000 each. According to the Center for Public Integrity, even Lewis said that he would feel "much better" if the institute's funding came from churches and foundations instead of corporations.

In January 1977, incumbent Democrat U.S. Congressman Andrew Young of Georgia's 5th congressional district resigned in order to become the U.S. Ambassador to the U.N. under President Jimmy Carter. In the March 1977 open primary, Atlanta City Councilman Wyche Fowler, Jr. ranked first with 40% of the vote, failing to reach the 50% threshold to win outright. Lewis ranked second with 29% of the vote. In the April election, Fowler defeated Lewis 62%–38%. After his unsuccessful bid for Congress in 1977, he accepted a position with the Carter administration as associate Director of ACTION, responsible for running the VISTA program, the Retired Senior Volunteer Program, and the Foster Grandparent Program. He held that job for two and a half years, resigning as the 1980 election approached. In 1981, Lewis was elected to the Atlanta City Council.

Since 1991, Lewis has been senior chief deputy whip in the Democratic caucus. A December 2009 report on privately financed Congressional travel by The New York Times found Lewis to be recipient of the most trips since 2007, with a total of 40.

He was challenged in the Democratic primary just twice: in 1992 and 2008. In 1992, he defeated State Representative Mable Thomas 76%–24%. In 2008, Thomas decided to challenge Lewis again, as well as the Reverend Markel Hutchins. Lewis defeated Hutchins and Thomas 69%–16%-15%.

John Lewis has been reelected 14 times. He has dropped below 70 percent of the vote only once. In 1994, he defeated Republican Dale Dixon by a 38-point margin, 69%–31%. He even ran unopposed in 1996 and from 2004 to 2008.

Lewis is honored with the 1997 sculpture by Thornton Dial, The Bridge, at Ponce de Leon Avenue and Freedom Park, Atlanta. Two years later, in 1999, Lewis was awarded the Wallenberg Medal from the University of Michigan in recognition of his courageous lifelong commitment to the defense of civil and human rights. In that same year he received the Four Freedoms Award for the Freedom of Speech.

Lewis's autobiography, Walking with the Wind: A Memoir of the Movement, co-written with Michael D'Orso, was published in 1998. A national bestseller, it won the Robert F. Kennedy Book Award, was selected as a New York Times Notable Book of the Year, was included on Newsweek magazine's list of "50 Books For Our Times," and was named Nonfiction Book of the Year by the American Library Association. His life is also the subject of a 2002 book for young people, John Lewis: From Freedom Rider to Congressman. In 2012, Lewis released Across That Bridge, written with Brenda Jones, to mixed reviews. Publishers Weekly's review said, "At its best, the book provides a testament to the power of nonviolence in social movements… At its worst, it resembles an extended campaign speech".

In 2001, the John F. Kennedy Library Foundation awarded Lewis the Profile in Courage Award "for his extraordinary courage, leadership and commitment to civil rights." It is a lifetime achievement award and has been given out only twice, John Lewis and william Winter (in 2008).The next year he was awarded the Spingarn Medal from the NAACP.

In March 2003, Lewis spoke to a crowd of 30,000 in Oregon during an anti-war protest before the start of the Iraq War. He was arrested in 2006 and 2009 and outside the Sudan embassy in protest against the genocide in Darfur. He was one of eight U.S. Representatives, from six states, arrested while holding a sit-in near the west side of the U.S. Capitol building, to advocate for immigration reform. The lawmakers' participation and subsequent arrest in the protest occurred despite the fact that the 2013 government shutdown was going on at the time. Lewis also led the 2016 House Democrats sit-in demanding that the House take action on gun control in the wake of the Orlando nightclub shooting and the failure of the United States Senate to act.

In 2006, he received the US Senator John Heinz Award for Greatest Public Service by an Elected or Appointed Official, an award given out annually by Jefferson Awards. In September 2007, Lewis was awarded the Dole Leadership Prize from the Robert J. Dole Institute of Politics at the University of Kansas.

At first, Lewis supported Hillary Clinton, endorsing her presidential campaign on October 12, 2007. On February 14, 2008, however, he announced he was considering withdrawing his support from Clinton and might instead cast his superdelegate vote for Barack Obama: "Something is happening in America and people are prepared and ready to make that great leap." Ben Smith of Politico said that "it would be a seminal moment in the race if John Lewis were to switch sides."

In October 2008, Lewis issued a statement criticizing the campaign of John McCain and Sarah Palin and accusing them of "sowing the seeds of hatred and division" in a way that brought to mind the late Gov. George Wallace and "another destructive period" in American political history. McCain said he was "saddened" by the criticism from "a man I've always admired," and called on Obama to repudiate Lewis's statement. Obama responded to the statement, saying that he "does not believe that John McCain or his policy criticism is in any way comparable to George Wallace or his segregationist policies." Lewis later issued a follow-up statement clarifying that he had not compared McCain and Palin to Wallace himself, but rather that his earlier statement was a "reminder to all Americans that toxic language can lead to destructive behavior."

In February 2009, forty-eight years after he had been bloodied by the Ku Klux Klan during civil rights marches, Lewis received an apology on national television from a white southerner, former Klansman Elwin Wilson.

On November 17, 2010, Lewis was awarded the First LBJ Liberty and Justice for All Award, given to him by the Lyndon Baines Johnson Foundation, and the next year, Lewis was awarded the Presidential Medal of Freedom by President Barack Obama.

Lewis met Lillian Miles at a New Year's Eve party hosted by Xernona Clayton. They married in 1968. Together, they had one son, named John-Miles. Lillian died on December 31, 2012.

In 2013, Lewis became the first member of Congress to write a graphic novel, with the launch of a trilogy titled March. The March trilogy is a black and white comics trilogy about the Civil Rights Movement, told through the perspective of civil rights leader and U.S. Congressman John Lewis. The first volume, March: Book One is written by Lewis and Andrew Aydin, illustrated and lettered by Nate Powell and was published in August 2013, the second volume, March: Book Two was published in January 2015 and the final volume, March: Book Three was published in August 2016.

Lewis is portrayed by Stephan James in the 2014 film Selma. He made a cameo appearance in the music video for Young Jeezy's song "My President", which was released in the month of Obama's inauguration.

The March series is used in schools across the country to teach some of the history of the Civil Rights Movement to students. In 2015, the series was selected as a First-Year Common reading text at colleges and universities such as University of Utah, Henderson State University, University of Illinois Springfield, Washburn University, and among others.

On September 19, 2016, Rep. John Lewis was awarded the Liberty Medal at the National Constitution Center. The prestigious award has been awarded to international Leaders from Malala Yousafzai to the Dalai Lama, Presidents George Bush and Bill Clinton and other dignitaries and visionaries. The timing of Lewis's award coincided with the 150th anniversary of the 14th amendment.

On January 13, 2017, during an interview with NBC's Chuck Todd for Meet the Press, Lewis stated: "I don't see the president-elect as a legitimate President." He added, "I think the Russians participated in having this man get elected, and they helped destroy the candidacy of Hillary Clinton. I don't plan to attend the Inauguration. I think there was a conspiracy on the part of the Russians, and others, that helped him get elected. That's not right. That's not fair. That's not the open, democratic process." Trump replied on Twitter the following day, suggesting that Lewis should "spend more time on fixing and helping his district, which is in horrible shape and falling apart (not to [...] mention crime infested) rather than falsely complaining about the election results," and accusing Lewis of being "All talk, talk, talk – no action or results. Sad!" Trump's statement about Lewis' district was rated as "Mostly False" by PolitiFact, and he was criticized for attacking a civil rights leader such as John Lewis, especially one who was brutally beaten for the cause, and especially on Martin Luther King weekend. A few days later, Lewis said that he would not attend Trump's inauguration because he did not believe that Trump was the true elected President.

In 2018, Lewis and Andrew Aydin co-wrote another graphic novel as sequel to the March series entitled Run. The graphic novel picks up the events in Lewis' life after the passage of the Civil Rights Act. The authors teamed with award-winning comic book Illustrator Afua Richardson for the work which is scheduled for release in August 2018. Nate Powell, who illustrated March, will also contribute to the art of Run.