Jennifer Tilly was born Jennifer E. Chan in Harbor City, California. Her father was a Chinese stockbroker and her mother an Irish-Canadian. Tilly is her mother's maiden name. Jennifer and her two sisters, Meg Tilly and Rebecca Tilly, were brought up in rural British Columbia, Canada. Jennifer began her acting career in her teenage years through a theatre program at Stephens College in Missouri.

Her breakthrough film role was as a singing waitress in The Fabulous Baker Boys (1989) in a part that was specially written for her by Steve Kloves. She was nominated for the Academy Award for Best Supporting Actress for her role as a hopelessly bad actress in Woody Allen's Bullets Over Broadway (1994).

Tilly gained some additional popularity in recent years for providing voice-over work as killer doll Tiffany for the Child's Play series of movies. In the most recent installment, Seed of Chucky, she plays a dual role, not only providing the voice for Tiffany but also playing an exaggerated version of herself. She played the wife of a murdered Italian Mafia son in Bella Mafia with Dennis Farina. Tilly has also appeared in Bound, which revolves around a lesbian relationship her character has with Gina Gershon.

Tilly is a semi-regular cast member on Family Guy, voicing the Griffin family's neighbor, Bonnie. She has also done vocal work for the film Monsters, Inc., the children's series Hey Arnold, Stuart Little and The Haunted Mansion, where she does the voice over for Madame Leota and works from the neck up. She has been active in the theatre, winning a Theater World Award for her performance in the off-Broadway play One Shoe Off.

Jennifer Tilly has 3 new projects for 2006, The Poker Movie, Intervention and a remake of The Initiation of Sarah for TV.

Her World Series of Poker championship bracelet can be seen on her left wrist.On June 27, 2005, Tilly won a World Series of Poker bracelet (and $158,625) in the Ladies' No-Limit Texas Hold 'Em event, outlasting 600 other players. She is the first non-poker celebrity to win a World Series of Poker event. She followed up this accomplishment on September 1, 2005 by also winning the third World Poker Tour Ladies Invitational Tournament held at the Bicycle Casino in Los Angeles.

Tilly has appeared in the GSN Poker Royale series. She appeared in the third season of Poker Superstars but was eliminated in the preliminary round.

Tilly played in the Celebrity Poker Showdown which aired June 14, 2006 on Bravo. Tilly was knocked out in third place by Bravo¡¯s internet poker champion Ida Siconolfi (the first non-celebrity to appear on the show) when her A¢À K¢¾ failed to improve against Ida's starting hand of K¢À K¢¼.

In a television interview, Tilly stated that at this point in her career she is more interested in pursuing poker than acting.

Tilly married The Simpsons producer Sam Simon in 1984, but they divorced in 1991.