In 1999, she made the decision to become an adult film actress and shot her first movie, which was directed by Raven. She signed a contract with the studio Sin City early in her career, but left the company after about a year and a half as “things did not work out.” She gained her first AVN Award in 2001, winning “Best Tease Performance” for her role in VCA Pictures' Shayla's Web. In 2003, she signed an exclusive contract with Wicked Pictures, after turning down offers from other companies. In 2004, during a HIV outbreak in the industry, she stated that she had only performed with men who wore condoms, although gave the opinion that “working without condoms in the industry is less dangerous than going home with someone who you just met randomly in a bar.” Her performance in Fluff and Fold, a romantic comedy set around a laundromat, earned her the 2005 AVN Award for “Best Actress, Video” and the 2005 XRCO Award for “Single Performance, Actress.” Along with comedian Jim Norton, Drake was chosen to co-host the 2007 AVN Awards, and stated “this is probably the greatest thing that ever happened to me.” At the awards, she won “Best Actress, Film” for her role in Manhunters, for which Drake trained as a bounty hunter during pre-production. Her directorial debut came in the 2008 film What Girls Like, having gained previous experience working as Brad Armstrong’s assistant director on titles such as 2007's Coming Home. She began writing screenplays during her tenure with Sin City, and has since penned films including Dating 101, Love Always and Just Between Us. In January 2009, she won her third “Best Actress” AVN Award, this time for her performance in Fallen, which she has described as “the best movie I have ever been in.” In the film, she plays a angel trapped on Earth after the death of a woman she was sent to protect. Around the time of the awards, she suffered a stress fracture to her left foot. With porn actress Kayden Kross, Drake co-hosted the 2009 XRCO Awards, at which her role in Fallen won the award for “Single Performance, Actress.” At the 2010 AVN Awards, Drake was inducted into the AVN Hall of Fame. She and Sunny Leone co-hosted the F.A.M.E. Awards in July 2010.

Drake has appeared in several television shows. She appeared in one episode of the short-lived TV series The Money $hot, and the pilot episode of Skin. She made an appearance, along with her former husband Evan Stone, in the HBO special Pornucopia: Going Down in the Valley. The pair appeared in an episode titled Love and/or Sex which pertained to couples working in the adult entertainment business. In November 2007, Drake was among several porn actors to be guests on The Tyra Banks Show episode, “A Day in the Life of a Porn Star.” In 2008, Drake, Kaylani Lei, and Mikayla Mendez shot a scene for the mainstream comedy movie, Barry Munday, in which they played themselves as judges in an air-guitar contest. Drake appears in the music video for the 2010 single “Telephone” by Lady Gaga featuring Beyoncé.

Her name is often spelled “jessica drake” (all lower case). Drake's story as to how this came about was she was signing autographs at a convention about three months after starting in the adult business using “Jessica Drake” (proper case) but she was unhappy with how it looked. After the convention, she experimented with various ways of signing and settled on the lower case version of her name.