In the early 1990s, she took her first major acting role as Sydney Andrews in the prime time series Melrose Place. The part was originally intended for only two episodes in season 1, but was developed into a full-time role for the subsequent seasons 2 to 5 (1993-97). Leighton left Melrose Place in 1997 at the end of her contract, and later appeared on Beverly Hills, 90210. Aaron Spelling created the role of wannabe actress Sophie Burns for her, and she received a six-figure salary per episode.
In 1999, Leighton appeared in the independent feature film Angels, Baby!, it received a small limited release late that year, that same year she appeared in the highly unsuccessful romantic comedy Seven Girlfriends and the thriller Clean and Narrow which was released direct to video in early 2000. On April 5, 2009 The Hollywood Reporter announced that Leighton would appear in the 2009 series Melrose Place, reprising her role as the presumed-dead Sydney, who will serve as landlord at Melrose Place.