In the early 1990s, Leighton's first on-screen jobs were in a commercial for Pizza Hut and Dep Hair Gel before taking her first major acting role as Sydney Andrews in the prime time soap opera Melrose Place.

[1] During the show's run, Leighton appeared on numerous magazine covers (including Entertainment Weekly and Rolling Stone and People).

[citation needed] Leighton left the show at the end of the fifth season in 1997, which saw her character Sydney being struck and seemingly killed by a car, only moments after her wedding to Craig Field, played by David Charvet.

She later starred in the indie film The Sky Is Falling with Dedee Pfeiffer and Eric Close before taking a break to have her son Jack Douglas.

From 2006–2007, after her FOX pilot Damages with Cole Hauser was not picked up, she made numerous prime-time guest appearances, on shows such as the ABC drama/comedy Boston Legal, Law & Order: Special Victims Unit, CSI: Miami, and Shark.

[5] Following her performance in the second season of Melrose Place, Leighton was featured on the cover of Entertainment Weekly's 1994 Fall TV Preview issue.

The role of Sydney Andrews, which she signed on to reprise in the 2009 Melrose Place spin-off, has been recognized by The Hollywood Reporter as "one of the most popular characters" from the original series.