The Miami Vice episode also featured a guest appearance by her future husband, actor Cameron Dye, one year before their marriage.

Previously, she was featured on the daytime soap opera All My Children as Louisa Sanchez, the Latina common-law wife of Mitch Beck (Brian Fitzpatrick) whose presence threatened to thwart his relationship with Hillary Martin (Carmen Thomas).

In 1990, San Giacomo played a supporting role as Julia Roberts's character's wisecracking roommate Kit De Luca in Pretty Woman.

She also appeared as Nadine Cross in the Stephen King miniseries The Stand with Rob Lowe, which landed them on the cover of the May 7–13, 1994 issue of TV Guide.

Needing to work, but not wanting to be away from her newborn son for months at a time, San Giacomo shifted to television in the role of hot-tempered, sassy journalist Maya Gallo in Just Shoot Me!

[9] Her character was partially based on an unproduced idea that executive producer Steven Levitan once had in mind for actress Janeane Garofalo when he was a writer for The Larry Sanders Show.

San Giacomo was cast in the starring role because the series was meant to center on her character; however, the show soon adopted an ensemble style.

San Giacomo's work during season 2 (1997–1998) earned her a Golden Globe Award nomination in 1998 for Best Actress in a Television Comedy or Musical.

San Giacomo was to have made her return to television on The WB's new drama Related in 2005, but the character was recast due to creative differences.

She made two more public appearances at the Crystal and Lucy Awards on 6 June 2006 and at the 3rd Annual Alfred Mann Foundation Innovation and Inspiration Gala on 9 September 2006.

In December 2011, San Giacomo appeared on the episode titled "Beards" on Hot in Cleveland as Caroline, Melanie's estranged sister.

[12] In 2021, she was listed as the board secretary of the international wheelchair-charity Momentum Wheels for Humanity,[13] and honorary chair of the Environment of People Foundation, Inc., a charity promoting music opportunities for children.