Andrea Thompson began her career as a voiceover artist, which continues today. Her first significant film role was in the 1987 film Wall Street. In 1989, she was cast on the soap opera Falcon Crest as the scheming Genele Ericson during the show's final season, and played photojournalist Maggie Dawson in the Season 3, Episode 2 of the series Quantum Leap. In 1991, she played Nurse Helen Caldwell in the comedy film Delirious. In 1993 she was cast on the series Babylon 5 as telepath Talia Winters. Thompson left the series in the middle of its second season.

Thompson moved on to join the cast of JAG midseason as Commander Alison Krennick, an aide to the Judge Advocate General of the Navy and direct supervisor of Harmon Rabb. She was among several actors who left the show when it was canceled by NBC after one season before CBS picked it up. She then went on to play Detective Jill Kirkendall on four seasons of crime drama NYPD Blue, leaving in April 2000 to pursue a career in journalism.

Thompson joined CNN Headline News as an evening anchor in June 2001.

Thompson had a recurring guest role as Doctor Nicole Duncan on the third season of the television series 24, first appearing on that show in November 2003. In 2007, she appeared in season two of Bones in the episode "Spaceman in a Crater". In 2009, she played Field Agent Anne Hudson in "Outfoxed", a season five episode of the series Criminal Minds.

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