Wuhrer's first television break was MTV's Remote Control (1987). She was a regular cast member of the television series Swamp Thing from 1991 to 1992. She also worked as a VJ on MTV during the same period. In 1993, she was a regular in the TV series Class of '96, where she played college student Robin Farr. From 1994 to 1995, she starred as Ariel Hunter in the long-running prime-time soap opera Beverly Hills, 90210.

During this period she appeared in The Adventures of Ford Fairlane (1990) and starred in Beastmaster 2: Through the Portal of Time (1991). In 1995 she also had a supporting role in the John Singleton film Higher Learning, followed by Thinner (1996), Anaconda (1997), and Kissing a Fool (1998).

Wuhrer returned to television in 1997 on the series Sliders as Maggie Beckett, joining the cast as a regular and staying until the series ended in 2000. Wuhrer also guested in the TV series Leverage.

Wuhrer signed a record deal with Rick Rubin and her debut album, Shiny, was released in 1999 by Del-Fi Records. In addition to her singing, she also wrote most of the songs on the album and played both the guitar and the flute on several tracks. She has not recorded another album since then.

Wuhrer was later voted #76 on the FHM 100 Sexiest Women of 2000, #73 in the FHM 100 Sexiest Women in the World of 2001 and #36 in Maxim magazine's 50 Sexiest Women Countdown of 1999. She posed semi-nude in Playboy magazine in August 2000 as their Babe of the Month and earlier considered multiple offers to appear fully nude throughout 1998. She was also #64 on Celebrity Skin's 100 Sexiest Stars of All Time and #4 in the Celebrity Nudity Database's Most Popular Actresses of 1999.

Later mainstream film roles include Berserker (2001) and Eight Legged Freaks (2002).

Her breast implants encapsulated during the filming of Spider's Web, so she had them removed in 2002. She later wrote an article for the September 2002 issue of Glamour magazine about the insecurities that led her to get implants early in her career, and the sense of self-acceptance she acquired. After its publication, she appeared on The Oprah Winfrey Show and discussed the pressure she received from a prominent record Producer to get the implants, during what she called "the era of the Video Vixen".

From February 3, 2005 through November 2005, Wuhrer joined the cast of the daytime soap opera General Hospital as FBI Agent Reese Marshall, the former love interest of mobster Sonny Corinthos and former best friend/rival of Carly Corinthos. Wuhrer's character died after suffering injuries in a train wreck. In January 2006, Wuhrer announced that she was suing General Hospital, claiming that she was fired because of her pregnancy. The case was resolved in December 2006.