Born in Chicago, Illinois, Siskel was raised by his aunt and uncle after both his parents died when he was ten years old. He attended Culver Academies, graduated in Philosophy at Yale University in 1967, where he studied writing under Pulitzer Prize-winning author John Hersey, who helped him land a job at the Chicago Tribune in 1969. In 1975, Siskel teamed up with Roger Ebert, film reviewer for the Chicago Sun-Times, to host a show on the local Chicago PBS station WTTW which eventually became Sneak Previews. Their "thumbs-up, thumbs-down" system soon became an easily recognizable trademark, popular enough to be parodied on comedy shows such as In Living Color and in movies such as Hollywood Shuffle and Godzilla. Sneak Previews gained a country-wide audience in 1978 when it was carried on PBS.

Siskel and Ebert left WTTW and PBS in 1982 for syndication. Their new show, At the Movies, was produced and distributed by Tribune Broadcasting, the parent company that owned the Chicago Tribune and WGN-TV. Sneak Previews continued on PBS for 14 more years with other hosts. In 1986, Siskel and Ebert left Tribune Broadcasting to have their show produced by the syndication arm of The Walt Disney Company. The new incarnation of the show was originally titled Siskel & Ebert & the Movies, but later shortened to Siskel & Ebert. At the Movies also continued a few more years with other hosts.

He spoke to students at the 1990 Academy of Achievement Summit in Chicago.