Maher is known for his political satire and sociopolitical commentary, which targets a wide swath of topics: religion, politics, bureaucracies of many kinds, political correctness, the mass media, greed among people and persons in positions of high political and social power, the lack of intellectual curiosity of the electorate, among many topics. He supports the legalization of marijuana and gay marriage and serves on the board of PETA. He is also a critic of religion and is an advisory board member of Project Reason, a foundation aiming to promote scientific knowledge and secular values within society. Maher currently ranks number 38 on Comedy Central's 100 greatest stand-ups of all time.

Maher was born in New York City, the son of Julie (née Berman), a nurse, and William Maher, Sr., a network news editor and radio announcer. He was raised in his Irish American father's Catholic religion, remaining unaware that his mother was Jewish until his early teenage years. He subsequently self-identified himself as ethnically half-Jewish. Maher's family stopped attending church services when Maher was thirteen, due to his father's disagreement with the Catholic Church's position on birth control.

Maher was raised in River Vale, New Jersey, and graduated from Pascack Hills High School in Montvale. He received his Bachelor of Arts in English and History from Cornell University in 1978.

Maher began his career as a stand-up comedian and actor, and he continues to act and tour occasionally. He was host of the New York City comedy club Catch a Rising Star in 1979. Thanks to Steve Allen, he began appearing on Johnny Carson's and David Letterman's shows in 1982. He made limited television appearances, including two separate appearances on Murder, She Wrote — notably, as Maher likes to point out, as two different characters. He has also appeared in several films, usually in a comic role. His feature film debut was in D.C. Cab (1983), and he has also appeared in Ratboy (1986), Cannibal Women in the Avocado Jungle of Death (1988), and Pizza Man (1991), among others.

Maher rose to prominence as the host of Politically Incorrect with Bill Maher, a late-night political talk show that ran from 1993-1997 on Comedy Central and later on ABC, until it was ultimately cancelled in June 2002. The show typically began with a topical monologue from Maher preceding the introduction of four guests, usually a diverse group of individuals from show business, popular culture, political pundits, political consultants, authors, and occasionally news figures. The group would then discuss topical issues selected by Maher, who, too, actively participated in discussions. Jerry Seinfeld, a regular guest on the show, stated that Politically Incorrect reminded him of talk shows from the 1950s and 60s "when guests interacted with eachother as much as with the host." Maher has described the show as "The McLaughlin group on acid."

Politically Incorrect has won an array of awards, including an Emmy Award for Oustanding Technical Direction, two CableACE awards for Best Talk Show Series, and a Genesis Award for Best Television Talk Show. Maher has earned numerous award nominations for his producing, writing and hosting of Politically Incorrect, including ten Emmy nominations, two TV Guide nominations, and two Writers Guild nominations.

ABC decided against renewing Maher's contract for Politically Incorrect in 2002, after he made a controversial on-air remark shortly after the September 11th attacks, whereby he agreed with his guest, conservative pundit Dinesh D'Souza, that the 9/11 terrorists did not act in a cowardly manner. Maher replied, "We have been the cowards. Lobbing cruise missiles from two thousand miles away. That's cowardly. Staying in the airplane when it hits the building. Say what you want about it. Not cowardly. You're right." Maher later clarified that his comment was not anti-military in any way whatsoever, referencing his well-documented longstanding support for the American military.

In the context of the sensitive aftermath of the attacks, such a remark was deemed too controversial for some corporate advertisers. Although some pundits, including conservative radio host Rush Limbaugh, came to Maher's defense in pointing out the distinction between physical and moral cowardice, several companies including FedEx and Sears Roebuck pulled their advertisements from the show, costing the show more than it returned. Ari Fleischer, the then White House Press Secretary for the Bush Administration, addressed the issue in response to a reporter's question about Maher's remark during a daily press briefing: "...they're reminders to all Americans that they need to watch what they say, watch what they do. This is not a time for remarks like that..."

The show was finally cancelled on June 16, 2002, despite the fact that the Sinclair Broadcast Group had dropped the show from its ABC affiliated stations months prior. On June 22, 2002, just six days after the cancellation of Politically Incorrect, Maher received the President's Award (for "championing free speech") from the Los Angeles Press Club. Maher has also sat on the board of judges for the PEN/Newman's Own First Amendment Award.

Maher's remarks on the cowardice of terrorists was not the first time he had sparked controversy on Politically Incorrect. In the same year, Maher was widely criticized for comparing dogs to retarded children: "But I've often said that if I had — I have two dogs — if I had two retarded children, I'd be a hero. And yet the dogs, which are pretty much the same thing. What? They're sweet. They're loving. They're kind, but they don't mentally advance at all.... Dogs are like retarded children." When another guest told him that her nephew was retarded and that she didn't think of him as a dog, he responded with "Maybe you should." He later apologized, stating "I make no excuses. I was wrong and what I said was hurtful to people and I feel terrible about it."