Alan Colmes was born in New York City. He attended local public schools and went to Hofstra University, where he graduated in 1971 with a Bachelor of Arts degree from its School of Communications. While at Hofstra, he worked at its radio station WRHU.

Colmes began his career in stand-up comedy. He developed his radio career in the Northeast, eventually working at stations such as WABC, WNBC, WHN and WEVD in New York, WNHC in New Haven, and WEZE and WZLX in Boston.

His radio career took off when WABC hired him for the morning drive time slot. He was billed as "W. Alan B. Colmes," as in the station's call sign. He moved to WNBC in 1987, but his tenure there would be short when, in 1988, NBC announced it would close its radio division. When WNBC went off the air for the last time on October 7, 1988, Colmes' was the last voice heard. He has been syndicated nationally, starting with his involvement with Daynet, a venture created by Colmes and other regional radio hosts. Daynet was sold to Major Networks, Inc., in 1994. Colmes kept his own show, which is distributed by Fox News Radio. He was well-known in New York when he was hired by Fox News CEO Roger Ailes in 1996. He was the co-host of Hannity and Colmes, beginning with the Fox News Channel launch on October 6, 1996 and ending on January 9, 2009. He also appeared live on Shovio.com's innovative new broadcasting technology, TalkBackTV.

Colmes's book, How Left is Right and Right is Wrong (ISBN 0-06-056297-8), was published in October 2003.

Colmes left Hannity and Colmes at the end of 2008. Fox replaced it with Hannity, premiering in January 2009. Colmes has continued as a commentator on Fox News, most often on The O'Reilly Factor, which precedes Hannity. He frequently appears with his sister-in-law, Monica Crowley, who is a conservative spokesperson. He is a frequent guest-panelist on Fox News' late-night satire program Red Eye w/ Greg Gutfeld.

While Colmes describes himself as a liberal and his Fox News biography touts him as "a hard-hitting liberal," he has sometimes been referred to disparagingly as a "token liberal" or a "Fox News liberal." Suspicions from fellow liberals that Colmes was not "one of them" were fueled by his statement to USA Today that he is "quite moderate."

During his run on Hannity and Colmes, Colmes was criticized for being less charismatic and telegenic than Sean Hannity, and just a "seat-filler" for the liberal side. Some newspapers reported him as being Hannity's "sidekick". Democratic Senator Al Franken criticized Colmes in his book, Lies and the Lying Liars Who Tell Them, saying he refused to ask tough questions during debates and neglected to challenge erroneous claims made by Hannity or his guests. Franken claimed that Colmes did not speak as much as Hannity during the show. Some critics questioned whether or not both hosts receive equal time to interview guests. Some of Colmes' liberal critics, notably commentators at Media Matters for America, praised him toward the end of the show's run. He began to cite their reports in interviews with some conservative guests on the program.

Bob Garfield, interviewing Colmes for On the Media in 2003, asked him if he was "the human straw man" and a "foil" rather than an equal of Hannity. Colmes replied that if the conservative members of the audience saw him that way, that was "their problem," and said "It's more fun for me to be in a situation like this than to preach to the choir."

Colmes is married to Dr. Jocelyn Elise Crowley, a professor of public policy at Rutgers University. Her sister is Monica Crowley, the conservative radio and television commentator.