In 1993, Playboy accepted Jenny as one of their models and promptly paid her $30,000 for her first photo shoot. Jenny was named Playboy’s Playmate of the Month, then Playmate of the Year, which garnered much media attention. She decided to capitalize on the exposure by making the move to Los Angeles in 1994, where she hosted Playboy’s uncensored music video show Hot Rocks.

In 1995, Jenny was chosen to host an MTV dating show called Singled Out. By 1997, she had developed a sketch comedy called The Jenny McCarthy Show. NBC producers liked what they saw, and signed Jenny up for her own short-lived sitcom, Jenny. That same year, McCarthy released her autobiography, Jen-X.

Jenny’s shtick as the blunt, buxom blonde unafraid to poke fun at her quirks was a deliberate attempt to stand out from the crowd in Hollywood. She says, "When I started on Singled Out I thought I'd make a point when that camera came on to do the opposite of what chicks that look like me do. So I started sticking my tongue out, picking my nose and making fun of it all and it seemed to work. So I ran with it."

In 1999, Jenny married actor and director John Asher. They had one son together, Evan Joseph, born on May 18, 2002. The pair split in 2005, and since then McCarthy has been in a relationship with comedic actor Jim Carrey. McCarthy has previously been involved with her manager, Ray Manzella, and also admitted to having a fling with porn star Jenna Jameson.

In 1999, Jenny starred in the film Diamonds, which was directed by her then-husband, John Mallory Asher. In 2000 she appeared in the movie Scream 3 alongside former Playboy Playmate, Pamela Anderson. Throughout the new millennium, Jenny has guest-starred on such series as Stacked, Charmed, The Drew Carey Show, Fastlane, and Just Shoot Me!.