Simultaneously, Adams had begun to establish a big screen career mostly in independents, beginning with parts in Richard Linklater's "Dazed and Confused" and "The Pros and Cons of Breathing" (both 1993). Adams appeared briefly as James Caan's daughter in "The Program" (also 1993) and had a two-line role alongside Parker Posey in "Sleep With Me" (1994). In "S.F.W." (also 1994), she played Stephen Dorff's ex-girlfriend and then appeared with Ben Affleck as one of the titular "Mallrats" (1995), directed by her off-screen companion Kevin Smith. Smith wrote and directed "Chasing Amy" (1997) for the actress. As Alyssa Jones, the bisexual comic book artist, Adams won the attention not only of screen co-star Ben Affleck but also of critics and audiences alike. Based on her success, she was cast as Vince Vaughn's love interest in "A Cool Dry Place" and opposite Adam Sandler in "Big Daddy" (both 1999).

Adams continued starring in low-budget indies, including Shirley MacLaine’s directorial debut, “Bruno” (2000), then starred Sally Field’s directorial debut, “Beautiful” (2000), playing the best friend of a Miss America hopeful (Minnie Driver) helping to hide her illegitimate daughter so she can win the competition. After reuniting with Kevin Smith for a small role in the unnecessary “Jay and Silent Bob Strike Back” (2001), she appeared in the crime drama “In the Shadows” (2001), a moody straight-to-video thriller about a hitman (Matthew Modine) sent to Hollywood to kill a stuntman (James Caan). Adams next costarred in “Harvard Man” (2001), playing an almost-30-year-old philosophy professor whose predilection for three-way sex further complicates the life of a Harvard student (Adrian Grenier) already neck-deep in drugs, gambling and an affair with a devious cheerleader-cum-mob daughter (Sarah Michelle Gellar). For “Dr. Dolittle 2” (2001), Adams voiced the character Squirrel, one of several furry creatures able to communicate with the good doctor (Eddie Murphy). She then turned to television for “On the Edge” (Showtime, 2001), a series of three futuristic short films woven together by a narrative involving an arrogant movie mogul forced to learn three life lessons after being taken hostage by a temp.

Adams returned to her indie roots for her next two features: “The Big Empty” (2003), a black comedy about a struggling actor (Jon Favreau) looking to score easy money by delivering a briefcase given to him by a mysterious stranger, and “Grand Champion” (2005), a heart-warming family movie in which she played a single Texas mother raising a young boy (Jacob Fisher) who kidnaps his prize-winning steer after it was sold to a man wanting to turn the heifer into barbeque. Then in “The Break-Up” (2006), the long-awaited, but much-maligned romantic comedy starring Vince Vaughn and Jennifer Aniston, Adams further complicates the break-up of her best friend (Aniston) with her louse boyfriend (Vaughn) by giving errant advice. Adams then made her screenwriting and directing debut with “Come Early Morning” (lensed 2005), a character drama about a 30-something woman (Ashley Judd) whose life of waking up with a hangover and a man she doesn’t want to know starts to change once she gets in touch with her family’s past—and with herself.