DeDePaiva made her debut in daytime television in November 1986, in the role of Chelsea Reardon on Guiding Light, which she held until January 1991. On December 17, 1993, DePaiva debuted on One Life to Live in the role of Blair, for which the actress would become most notable. She would remain with One Life to Live until the series finale on January 13, 2012.
In January 2012, just prior to One Life to Live airing its series finale, it was announced that DePaiva, along with co-stars Kristen Alderson, Michael Easton, and Roger Howarth, would join the cast of ABC's sole remaining daytime soap opera General Hospital, where she would continue her portrayal of Blair. She made her debut on General Hospital on March 2, 2012. Of the four actors who crossed over following the end of One Life to Live, DePaiva was the only one whose appearence was short-term, and she last aired on March 13, 2012.