Janeane Marie Garofalo was born on September 28, 1964, in Newton, New Jersey, to Joan, a secretary, and Carmine Garofalo, an Exxon executive. She is of Italian and Irish descent. Garofalo grew up in various places including Ontario, California, Madison, New Jersey, and Houston, Texas.

She attended Madison High School and later graduated from Providence College with degrees in history and American studies. Inspired by David Letterman, she began performing stand-up comedy in 1985 and quickly developed a reputation for her sharp wit and dry, sarcastic humor, becoming a prominent figure in alternative comedy.

Her early television career began with the 1992 Fox sketch comedy show "The Ben Stiller Show," which she joined alongside friends like Bob Odenkirk and Andy Dick. Her breakout role came as Paula on HBO’s "The Larry Sanders Show," earning her two Primetime Emmy nominations for Outstanding Supporting Actress in a Comedy Series in 1996 and 1997.

She briefly joined "Saturday Night Live" in 1994 but left after six months, citing dissatisfaction with the show’s environment and style of comedy. She also worked as a correspondent on Michael Moore’s "TV Nation" and appeared in many films throughout the 1990s and early 2000s, including "Reality Bites," "Romy and Michele's High School Reunion," "The Truth About Cats & Dogs," "Dogma," and "Mystery Men," often portraying smart, cynical, and acerbic characters that matched her stand-up persona.

In addition to acting, she has been a vocal political activist and commentator, known for her progressive views and criticism of religion and politics, which she has expressed through various media, including her time as a co-host on Air America Radio's "The Majority Report."

She has continued to work steadily in television, film, and voice acting, including guest roles on shows like "The West Wing," "24," and animated projects such as "Ratatouille."