Talley was born in Chcago. In her twenties, she performed improv comedy in Chicago at the Improv Institute and The Second City. Previously, they were both cast members of the short-lived Company FOX Network sketch comedy show The Edge from 1992 to 1993. They also appeared together in the 1996 Smashing Pumpkins video "Tonight" as the married couple who take a honeymoon on the moon. Talley's vocal work includes playing Karen, computer wife of Plankton on SpongeBob SquarePants, as well as Gretchen, the tomboyish alligator Squirrel Scout, the scholarly giraffe named Nina, and the largely angry warthog named Ms. Mucus on Camp Lazlo. She also voices Sarah Dubois on the Adult Swim show, The Boondocks. Also, she voiced Lindsey Gunt on Nickelodeon's Herdy & Gerdy. Since Mr. Show's run she has also appeared in minor roles in several films such as Little Miss Sunshine and Sky High, the latter of which she appeared with her husband. Talley has also been known to voice Number 318 on Codename: Kids Next Door and Giselle in Stripperella. Her voice was featured in the videogame Portable Ops. She also did Nosey on a Rocko's Modern Life on Nickelodeon. She also was in one episode of Frasi She is also the wife of voice actor Tom Kenny who also appeared regularly on Mr. Show. Talley and Kenny have two children, a boy and a girl.
- Jill Talley is the voice actress of Sarah Dubois and among other women on the Boondocks.