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Kathy Griffin was born and raised in the Chicago suburb of Oak Park, Illinois, where her father John worked in an electronics store and her mother Maggie raised three boys and two girls — Kathy is the youngest sibling — and assisted in a hospital's administrative office. Her parents retired to California after Kathy Griffin finished high school, and she eventually performed with the Los Angeles improv comedy troupe the Groundlings.

She went on to perform stand-up comedy and to do some acting, breaking into film with the supporting role of "Connie" in the Brooke Adams horror movie The Unborn (1991). She gradually amassed such early TV and film credits as a role in comedian Julie Brown's Medusa: Dare to Be Truthful (1992), an HBO parody of the backstage film Madonna: Truth or Dare (1991); two appearances as the character Susan Klein on NBC's The Fresh Prince of Bel-Air, her TV sitcom debut; fellow comic Bob Goldthwait's movie Shakes the Clown (1992); and an episode of ABC's divorce-attorney series Civil Wars, Kathy Griffin's dramatic-series debut.

After starring in an HBO Half Hour Comedy Special, Kathy Griffin reached a measure of fame in 1996 playing the acerbic colleague of Brooke Shields' title character on the NBC sitcom Suddenly Susan. In 1998, Kathy Griffin starred in her first one-hour special, HBO's Kathy Griffin: A Hot Cup of Talk. She went on to a comedy and television career poking dissatisfied fun at her relatively modest place in the Hollywood hierarchy, frequently appearing in such self-consciously tacky projects as the reality show competition Celebrity Mole Hawaii — in which she won the 2003 edition after undergoing such experiences as walking over hot lava in her bare feet. Kathy Griffin has also done voiceover work on a wide variety of projects, including Dilbert and Spider-Man animated series.

In 2005, Kathy Griffin starred in her solo reality show Kathy Griffin: My Life on the D-List, on the cable network Bravo. The show also featured her husband Matt Moline and her personal assistant Jessica Zajicek. The second-season premiered on June 6, 2006.

At a time when stand-up comedy was turning, to an extent, from punch-line orientation to humorous social commentary and satire, Kathy Griffin established her career with observations about celebrity culture and fame. Her stage act invariably consists of recounting fictional or embellished events involving celebrities. Her favorite celebrity topics are plastic surgery, drunkenness, substance abuse, snooty attitude, eating disorders, and stars whose sexual orientation is disputed. Among Kathy Griffin's staples are Clay Aiken, Whitney Houston, Celine Dion, Gwyneth Paltrow, Star Jones, and Anna Nicole Smith. Most of all, she is the butt of her own humor, particularly with regard to her plastic surgery and stagnant D-List status.

Kathy Griffin frequently mentions her admiration for gay men, and in her live performances acknowledges her large gay following.

Kathy Griffin met Washington, D.C. native Matt Moline (born c. 1970) on a blind date in July 1999. They were engaged in Punta Mita, Mexico on 23 September 2000. They married in Los Angeles atop the Hollywood 360 Degrees Restaurant in February 2001. Brooke Shields served as Kathy Griffin's maid of honor. On September 27, 2005, Kathy Griffin filed for divorce citing irreconcilable differences. She and Moline reconciled in December 2005 (announced on 10 Feb 2006). Their divorce was finalized on May 15, 2006, but Moline and Kathy Griffin remain together in Los Angeles.

Moline has an IT consulting firm in Los Angeles, Moline Systems [1]. Kathy Griffin stated on her show that her contract has a clause that states her husband is to accompany her on all performances.

Kathy Griffin's mother Maggie Griffin often appears on her daughter's TV series.