In April 1997, Monaco became the Playboy Playmate of the Month. Throughout her tenure with Playboy in the 1990s, Monaco was also featured in many Playboy Special Edition publications.

Monaco made numerous cover appearances in other magazines such as FHM and Maxim. Along with her Maxim feature in 2005, the magazine also awarded her 13th place on their annual Hot 100 List in May 2006.

Monaco's first television role was on the nighttime drama Baywatch from 1997 to 1998. In addition to playing the role of Susan on the show, Monaco also was Carmen Electra's body double at times, as Electra could not swim[citation needed]. Monaco also had minor roles in the late 1990s films BASEketball, Idle Hands, and Mumford.

Monaco had two roles on the supernatural television soap opera Port Charles: Olivia “Livvie” Locke Morley (1999–2003) and Tess Ramsey (2002–2003). When that program ended, she joined the cast of soap opera General Hospital as Samantha “Sam” McCall in September 2003.

In 2003, Monaco was nominated for a Daytime Emmy Award for Outstanding Supporting Actress in a Drama Series for her role on Port Charles. In 2006, Monaco was again nominated for a Daytime Emmy, this time for Outstanding Lead Actress in a Drama Series for her role as Sam McCall on General Hospital. In 2006, Monaco also co-hosted the 33rd Annual Daytime Emmys, with Dancing with the Stars host Tom Bergeron.

In March 2009, Monaco was chosen by Donald Trump and Paula Shugart to be one of the judges for the 2009 Miss USA pageant.

Monaco was a cast member, and the season winner, on the ABC reality television series Dancing with the Stars, during its first season in 2005. Among the events that she experienced prior to her victory were a disappointing first episode in which she received unvarnished criticism from judge Bruno Tonioli, and a near-wardrobe malfunction in which the skimpy strap on her dress during a Latin dance number came apart.

In February 2009, Monaco expanded her dancing résumé with Peepshow, a burlesque act directed by Tony Award-winning director Jerry Mitchell that plays at the Planet Hollywood Resort and Casino in Las Vegas. Monaco starred as Bo Peep, a precocious character who discovers her sexuality throughout the show. Monaco starred alongside British pop diva and fellow Dancing with the Stars contestant Mel B, aka Scary Spice. Both Monaco and Mel B left the show in late June 2009.

Monaco is a fan of extreme sports, and participated in the all-women's Hi-Tec Racing Series, which consisted of 12 miles of off-road running, 3–4 miles of kayaking and 12–15 miles of mountain biking, interspersed with a Marine-style obstacle course. Monaco's team came in second.

On April 25, 2009, Monaco's apartment at the Planet Hollywood Resort and Casino was ransacked by burglars. It is unclear what was taken. On Sept. 8, 2009, Merrill Wetter was sentenced to 12 to 30 months in jail after pleading guilty with no contest after being caught by surveillance tape. Wetter is to pay Monaco a reported $5,000 restitution, a $25 court fee as well as $150 DNA Fee. Wetter had broken into Monaco’s penthouse while Monaco was in the bedroom and had hidden behind the bed at the time of robbery in April 2009. Monaco is a vegetarian. She has recently broken off her relationship with her highschool boyfriend of 18 years.