Janney's first roles on television were as comedic foils on soap operas: she first played Vi Kaminski for a short time on As the World Turns, following up with a two-year stint as one of the Spaulding maids, Ginger on Guiding Light. In the spring of 1994, she appeared in the season finale of Law & Order, as a reluctant witness against a member of the Russian mob. This episode was also notable as Michael Moriarty's final episode in the series.

Janney has appeared in a number of films with roles of various sizes, including the 1990s films American Beauty, The Object of My Affection, Big Night, The Impostors, Drop Dead Gorgeous, The Ice Storm, Primary Colors, 10 Things I Hate about You, and Private Parts, and the 2000s films Nurse Betty, The Hours, The Chumscrubber, How to Deal, Winter Solstice and a considerable role in the animated movie, Finding Nemo, voicing Peach, the starfish. In 2006, Janney had carried notable roles in the movies, Margaret and Over the Hedge, an anima