She initially became known for her role as Annie Dutton on the CBS soap opera Guiding Light from 1994 to 1998. Watros' character began as a heroine, but she gained notice and critical acclaim when her character's rivalry with Reva Shayne (played by Kim Zimmer) led her to become a scheming villianess. In 1998, Watros won a Daytime Emmy Award as "Outstanding Lead Actress" for her role on Guiding Light.

In 1998, Watros briefly filled in for Jensen Buchanan as Victoria Hudson McKinnon on Another World while Buchanan was on maternity leave.

She is also known for her TV role as Erin Fitzpatrick on Titus from 2000 to 2002 and Kellie Newmark on The Drew Carey Show from 2002 to 2004. On Titus, she broke through as a comedic actress, playing the real-life fiance of the title character. According to the DVD commentary, Erin was originally supposed to be more like Tommy in the series (worrysome, neurotic), and Tommy was supposed to be more like how Erin was (strong, supportive). The characters' personality changes were made a week before the pilot was shot. After Titus was canceled, she took on the role of Kellie Newmark on The Drew Carey Show, as a replacement for the departure of Christa Miller. As a welcoming gesture, Drew Carey sent flowers to her on a weekly basis.

From 2005 to 2006, she is a cast member on the popular ABC series Lost. She played psychologist Libby, a member of the "Tailies", a group of survivors of the plane crash who were in the tail section of the plane (and not seen during Season One). Towards the end of the season (in the episode Two for the Road), Libby was shot and killed by Michael Dawson (played by Harold Perrineau) along with Ana-Lucía Cortez (played by Michelle Rodriguez).

Watros overcame a serious disease as a teenager; she was diagnosed with Idiopathic thrombocytopenic purpura, an autoimmune disease of the blood. It required several years of chemotherapy and a splenectomy. In an interview in the Season 3 DVD of Titus, she stated that she had lost her hair and gained over 100 pounds as a result of this disease.

Watros has had a complicated history with Guiding Light co-star Kim Zimmer. Zimmer and Watros met when they co-starred in an off-Broadway show, "Four Dogs and a Bone" by John Patrick Shanley. Although there is no long-standing rivalry, working in close quarters apparently caused a serious rift between them when they both appeared on Guiding Light. In particular, a physical altercation between the two actors was captured on tape during filming of a Guiding Light episode.

Watros is married to Curtis Gilliland and has twin daughters, Emma Rose and Sadie Anna (b. July 14, 2001).

Watros and her Lost co-star Michelle Rodriguez were each pulled over and arrested on the morning of December 1, 2005 in Kailua, Hawaii, where Lost is filmed. Both actresses were charged with drunk driving. At trial, Watros plead guilty and was ordered to pay a fine and go into counseling. Five months later both characters in the show were killed, leading some fans and TV pundits to suggest it was punishment for their arrests. Rodriguez and the producers have denied this, saying it was to be so from the beginning.