McCarthy, a cousin of actress Jenny McCarthy, was born in Plainfield, Illinois. She graduated from Joliet Catholic Academy (Formerly St. Francis Academy) in Joliet, Illinois. Her career started with stand-up comedy and includes film, television and theater.

She has had small roles in the films Disney's The Kid, Charlie's Angels, Go, The Third Wheel and The Life of David Gale. She also did voice work in three episodes of Kim Possible, where she played DNAmy. McCarthy is a member of the Los Angeles-based Groundlings improvisational comedy troupe. In 2007, she acted opposite Ryan Reynolds in The Nines, written and directed by John August. McCarthy also made a cameo in Charlie's Angels: Full Throttle.

McCarthy married her longtime boyfriend, actor Ben Falcone, on October 8, 2005. They have a daughter, Vivian, born May 5, 2007. Her pregnancy was written into the last season of Gilmore Girls.

She co-starred in the romantic comedy The Back-Up Plan.