[2][4] Early in her acting career, Littleford worked in improvisational theatre with the Chicago City Limits group, founded a sketch comedy troupe, and wrote her own one-woman show, This Is Where I Get Off, which she performed with the Circle Repertory Company.

[7] She has guest-starred on numerous television programs beginning in the late 1990s: The West Wing, Family Guy, and Frasier.

Littleford starred in the Disney XD original show I'm in the Band, the 2010 Disney Channel film Starstruck, and played Suzanne Berger on MTV's The Hard Times of RJ Berger, Dana on ABC's Desperate Housewives, and the realtor on The Fosters.

More recently, she had a starring role as Ellen Jennings in the Disney Channel original series Dog with a Blog and a guest appearance on Dead to Me on Netflix.

In 2021, Littleford was in the film Senior Moment starring William Shatner, Jean Smart and Christopher Lloyd.