Brown served as San Francisco mayor from January 8, 1996 (after defeating incumbent Frank Jordan), until January 8, 2004; he could not run for mayor again due to term limits, so he was succeeded by fellow Democrat Gavin Newsom. Brown had previously been a member of the California State Assembly from 1964-95; he was Speaker of the Assembly from 1981-95. In 1995 the Democrats lost control of the Assembly to Republicans led by Jim Brulte, but he soon regained control by making a deal with Republican defectors Doris Allen and Brian Setencich, both of whom were elected by the Democratic minority. During their tenures, Brown was the de facto Speaker. He graduated from San Francisco State University and the Hastings College of the Law.

Brown's long service in the Assembly, coupled with that body's tenure system for leadership appointments, gave Brown almost complete control over the California Legislature by the time he became Assembly Speaker. Brown was extremely popular in his home of San Francisco, though unpopular in the rest of the state. Nevertheless, he wielded great control over statewide legislative affairs and political appointments, making his removal from the Speakership politically difficult. Partially to remove Brown from his leadership position, Californians passed a state constitutional amendment imposing term limits on state legislators. After term limits put Brown out of office, the Assembly re-structured their rules, giving most of the powers formerly held by the Speaker to a leadership committee made up of senior members of both major parties.

In 1995, Brown left the State Assembly to run for Mayor of San Francisco against incumbent Frank Jordan. Brown easily defeated Jordan, and went on to serve two terms as Mayor.

Brown's flamboyant style made him so well-known as the consummate politican that when an actor playing a party politician in 1990's The Godfather Part III didn't understand director Francis Ford Coppola's instruction to model his character after Brown, Coppola fired the actor and hired Brown himself to play the role. Brown later appeared in 2000's Just One Night as a judge. He has also played himself in two Disney films, George of the Jungle and The Princess Diaries, and the 2003 Universal release "Hulk" (as the mayor of San Francisco).

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

Since January 2006, Brown has co-hosted a morning radio show with comedian Will Durst on a local San Francisco Air America Radio affiliate. He also makes a weekly podcast.