Cardellini made her series regular debut on the ABC Saturday morning live-action children's series "Bone Chillers" during the 1996-1997 season, and was additionally featured in 1997 episodes of "Clueless" (UPN), "Step by Step" (CBS), "Pacific Palisades" and "3rd Rock From the Sun" (both NBC). She hit the big screen for the first time with a supporting role in the 1997 comedy "Good Burger" and could next be seen in the college campus dark comedy "Dead Man On Campus", playing the silent girlfriend of a high-strung and violent student (future "Freaks and Geeks" co-star Jason Segel), whose roommates use his often vacant room to house a series of troubled undergraduates in the hopes of landing the 4.0 GPA offered to the suitemates of a suicidal student.

As one of the victims of masochistic internet predator Captain Howdy, Cardellini was featured in the thriller "Dee Snider's Strangeland" (1998) and was a prominent and striking figure on the theatrical poster and video cover, making her face (albeit with sewn together lips) more familiar to the moviegoing public. More TV work followed, including recurring parts on two series during the 1998-99 season: ABC's "Boy Meets World", as the girl who could inadvertently break up uber-couple Cory (Ben Savage) and Topanga (Danielle Fishel); and as a co-worker of one of the "Guys Like Us" (UPN). She took a supporting turn in the latter network's TV-movie drama "Dying to Live", portraying the spunky sidekick of a deceased girl who is exacting justice on her attacker through the help of an angel, before turning in a strong performance in AMC's miniseries "The Lot" (1999), as June, a young starlet in this fictionalized look at small time Hollywood in 1937.

Next up was a regular role on "Freaks and Geeks", where Cardellini served as the bridge between the two titular high school outcast factions as new social dropout (and aspiring 'freak') Lindsay Weir, the academically gifted sister of awkward freshman (and 'geek') Sam Weir (John Daley). Looking to belong somewhere and unsatisfied with her honor student lifestyle, Lindsay takes a walk on the freak side, making friends with intense drummer Bill (Jason Segel) and nihilistic rebel Daniel (James Franco). The series, noted for its realistic portrayal of high school circa 1980, received a great deal of advance buzz, and Cardellini's sympathetic spot on portrayal of a teenager searching for a place to fit in garnered critical praise and raised her profile considerably. She also gained considerable exposure and popularity with her role as Velma in 2002's live-action adaptation of "Scooby-Doo" where Cardellini played alongside teen heavyweights Sarah Michelle Gellar, Freddie Prinze Jr. and Matthew Lillard (the cast returned for the 2004 sequel).