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).

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.