Colmes was born to a Jewish family in New York City. He grew up in Lynbrook, New York on Long Island, 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.

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 NBC announced in 1988 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 had 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 was distributed by Fox News Radio. He was hired by Fox News CEO Roger Ailes in 1996. He was the co-host of Hannity & 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 new broadcasting technology, TalkBackTV.

Colmes’ debut non-fiction book, Red, White & Liberal: How Left is Right and Right is Wrong ( ISBN 0-06-056297-8), was published in October 2003. It tackles issues such as civil rights, the war on terror, and the perceived liberal media bias. Interspersed throughout are actual emails from Hannity & Colmes viewers, reprinted verbatim.

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 left Hannity & Colmes, with Fox replacing it with Hannity, in January 2009. Colmes continued as a commentator on Fox News, most often on The O’Reilly Factor where he frequently appeared with his conservative sister-in-law, Monica Crowley. He was also an occasional guest-panelist on Fox News’ late-night satire program Red Eye w/ Greg Gutfeld.

On January 5, 2009, the beginning of his last week on Hannity & Colmes, Colmes was a guest on The Colbert Report in a spoof called “Colbert & Colmes,” which parodied criticisms of Hannity & Colmes. In addition to being given a list of pre-approved responses to Stephen Colbert’s opinions and forced to sit on a stool (making him appear shorter than his co-host), Colmes’ face was covered by the on-air graphics while Colbert discussed issues of the day. Colbert “fired” Colmes by the end of the show for pointing out fallacies in his logic.

While Colmes described himself as a liberal and his Fox News biography touted him as “a hard-hitting liberal,” he has sometimes been referred to disparagingly as a “token liberal” or a “Fox News liberal”. Colmes told USA Today that he considered himself “quite moderate.” In an article he wrote in 2013, Colmes described himself as “very liberal”.

Colmes died of lymphoma at the Memorial Sloan Kettering Cancer Center in Manhattan on February 23, 2017, at the age of 66.