In 2002, Drake married fellow porn actor Evan Stone; they later divorced in 2004. As of 2009, she was living with Wicked Director and performer Brad Armstrong, her partner for six years. She has stated that she wishes to keep her personal relationships out of the spotlight. Her brother and father were more supportive of her career choice than her mother.

In 2004, during an 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.

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.

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." She and Sunny Leone co-hosted the F.A.M.E. Awards in July 2010. Drake was inducted into the AVN Hall of Fame in 2010 and the XRCO Hall of Fame in 2011. Jessica Drake's Guide to Wicked Sex: Anal Edition (Wicked Pictures) was named "Specialty Release of the Year" at the 2012 XBIZ Awards.

Drake teaches sex education seminars and workshops around the world, including addressing a class of licensed therapists at UCLA on May 3, 2012 and speaking on a panel at CatalystCon West sexuality conference. In February 2014, Drake spoke on a panel with fellow Actress Tasha Reign during the University of Chicago's Sex Week where they were featured on a panel entitled Jessica Drake: From Porn to Sex Ed.

Drake, along with her husband actor Brad Armstrong, were interviewed for a 2014 story in Cosmopolitan magazine about costume design in adult films. In April 2014, Drake was part of discussion panel at the USC School of Cinematic Arts titled "The Piracy of Sex." The event featured Drake and copyright enforcement Activist Nate Glass and was hosted by David Lerner, Ph.D.

Seventeen days before the United States presidential election, 2016, Drake became the 11th woman to accuse Donald Trump, the 2016 Republican nominee, of sexual misconduct. On October 22, 2016, Drake and feminist civil rights attorney Gloria Allred held a news conference in which Drake accused Trump of having sexually assaulted her and two acquaintances nearly ten years prior. Drake said that she met Trump at her company's booth during a charity golf tournament at Lake Tahoe in 2006. Drake claims that she was invited to meet with Trump, at his hotel suite and since she was "uncomfortable going alone" she brought along two women friends. Describing the meeting with Trump, Drake recounted that "He grabbed each of us tightly, in a hug and kissed each one of us without asking permission." Drake stated that she and her friends left the suite after 30–45 minutes. Shortly thereafter, Drake received multiple phone calls from Trump or his associate, requesting that she join him in his suite for $10,000, and offering to fly her on his jet plane back to Los Angeles. She said she declined his offers. At the press conference, Drake displayed a photo of herself and Trump together on the Lake Tahoe golf course.

In January 2018, Drake's publicist, Josh Ortiz, commented that Drake had signed a non-disclosure agreement regarding “any and every mention of Trump”. On the following day, Ortiz however retracted his words by reading a statement supplied by Drake's Lawyer, which stated that Ortiz had no knowledge of any non-disclosure agreement signed by Drake.

Again in February, Drake along with fellow Actress Tasha Reign spoke on a panel titled Porn, Prostitution, and Censorship: The Politics of Empowerment at Moore Hall at the University of California at Los Angeles (UCLA), along with UCLA Distinguished Lecturer Dr. Christopher Mott. The annual panel is sponsored by the Social Awareness Network for Activism through Art (SANAA) in honor of Eve Ensler’s V-Day Organization. Ensler’s The Vagina Monologues is an annual presentation on women’s issues.