Swanson started in TV advertising roles, and went on to make several one-off appearances in TV series such as Cagney and Lacey and Alfred Hitchcock Presents. In 1986, she debuted on the big screen in two John Hughes films: Pretty In Pink, in a non-speaking role, and Ferris Bueller's Day Off as a character who announces a convoluted excuse for Ferris' absence in class. Her first starring role was later in 1986, in Wes Craven's Deadly Friend. The next year she played Cathy in the adaptation of V. C. Andrews' best-seller Flowers in the Attic.

By 1990, Kristy Swanson had made many television appearances, including multiple appearances in Knots Landing (1987-1988), Nightingales (1989), her first starring role in a TV series, although it only lasted a season, and a shortlived Burt Reynolds vehicle called B.L. Stryker (1989).

Throughout the 90's she centered mostly in films. She played the title role in the 1992 movie Buffy the Vampire Slayer, which was a box office bomb but had a profitable rental life. She appeared in both starring and supporting roles in movies such as Hot Shots!, The Program, The Chase, or her most critically acclaimed role, that of Kristen Connor, a student discovering her sexuality in John Singleton's Higher Learning. She also appeared in the film adaptation of the comic-book The Phantom and the black comedy 8 Heads in a Duffel Bag, with Joe Pesci. Most of these films failed at the box office, and she reverted to TV work in the late 90's.

In the 1998-1999 season of Early Edition, Swanson played Erica Paget, a love interest of the main character, Gary Hobson. In 1999 Swanson played Vanessa, the girlfriend of Adam Sandler in the movie Big Daddy. In 2000, she returned to a television series, as the star of Grapevine, a revamp of a 1992 TV series. It was cancelled after 5 episodes.