Thompson was married to David Guc (1987–90), and to Babylon 5 costar Jerry Doyle (1995–97). She has a son named Alec (b. 1992).

Thompson started to prepare for her journalism career in 1999, by earning her GED and working arduously for one year with Jack Hubbard, associate Director of Stanford University's News Service and a veteran Journalist of CBS News. During this time, she also took a writing seminar with KGO-TV's feature reporter Wayne Freedman. She began her work with CBS affiliate KRQE in Albuquerque, New Mexico as a general assignment correspondent for $26,000 per year.

Thompson moved on to join the cast of JAG midseason as Commander Alison Krennick, an aide to the head of the Judge Advocate General of the Navy. 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. CNN had laid off 400 of 4000 employees in January, and was refocusing on personalities to draw in younger viewers. "A lot of people gave her credit for leaving her career to pursue journalism," said one CNN insider. Her first words on-screen as anchor were "Hi, I'm Andrea Thompson, and unless you've been living in a cave, you probably already know that." Her hiring generated controversy in journalism circles, mostly because Thompson had just one year of journalism experience at that point. Nude pictures and videoclips of Thompson taken from her 1980s-era movies also began circulating on the Internet, causing some embarrassment for CNN. Thompson left the network in March 2002. It was speculated at the time that the long days kept her from her nine-year-old son. During an appearance in January 2003, she made a statement indicating she left CNN because she disagreed with the way the news was handled, "Basically... you just give the viewers enough to scare the hell out of them, and not any real valuable information. And we saw so much of that after Sept. 11 that I thought was, frankly, irresponsible."

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".