Rachael Harris was born in Worthington, Ohio. Rachael Harris graduated from Worthington High School. She went on to graduate from Otterbein College, in 1989, majoring in theatre.

Rachael Harris performed with the Los Angeles, California, improvisational comedy troupe the Groundlings, and taught for a time with the Groundlings school. She debuted on television in a 1993 episode of SeaQuest DSV.

Rachael Harris film credits include roles in Best in Show, A Mighty Wind, For Your Consideration, Starsky & Hutch, Kicking & Screaming, and Daddy Day Care. In the 2009 comedy The Hangover she plays Melissa, girlfriend to Ed Helms.

Rachael Harris previously co-starred with Helms on the Daily Show. In 2010, she played Greg`s mom in the film Diary of a Wimpy Kid.