Before entering politics, Flynn was an All-American basketball player at Providence College, was selected Most Valuable Player in the 1963 National Invitation Tournament (NIT) during his senior year, and was the last player cut from the then-World Champion Boston Celtics.

Flynn began his political career as a Democratic member of the Massachusetts House of Representatives from 1971 to 1979, representing the South Boston neighborhood during the turbulent busing crisis of the early 1970s. He later served on the Boston City Council from 1978 to 1984, before successfully running for Mayor of Boston in 1983. He was reelected in 1987 and again in 1991.

Flynn, a life-long pro-life activist, was instrumental in drawing the pro-life, Catholic vote to pro-choice Governor Bill Clinton of Arkansas in his 1992 bid for the White House against incumbent George H. W. Bush. In 1993, Flynn resigned during his third term as mayor when he was appointed by Clinton to serve as U.S. Ambassador to the Holy See.

Following his service as ambassador, Flynn ran unsuccessfully for Massachusetts's 8th congressional district seat that was being vacated by Joseph Patrick Kennedy II in 1998.

While serving as mayor, Flynn played himself in the Cheers episode "The Stork Brings the Crane". In the episode Flynn has his entourage take away Cliff Clavin, who writes Flynn once a week.

In 1999, Flynn became president of Catholic Alliance, a nonpartisan Catholic advocacy group. Irish Echo Online - News In this role, while remaining a Democrat, he and the Catholic Alliance endorsed George W. Bush in the 2000 presidential election. The Wall Street Journal Online - Dispatch He became president of another Catholic political advocacy organization, Your Catholic Voice. Flynn left this group to start Catholic Citizenship, serving as its National Chairman from 2004 until 2008. In 2010, he supported the successful candidacy of Republican Scott Brown for the Massachusetts Senate.

In 2007, he was named Grand Marshall of the 246th consecutive New York St. Patrick's Day Parade.

Flynn is the co-author of two books: