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In 1985, Swanson made her professional debut in the Prince video Raspberry Beret. She and Prince were friends. He wrote a song entitled "Palomino Pleasure Ride" for her. In 1987, Swanson made her feature debut in the opening scene of Lethal Weapon. She played Amanda Hunsaker, who falls to her death from a building onto the hood of a car. She performed this free-fall stunt from 35 feet into an airbag under the training of stuntman Dar Robinson. Lethal Weapon would be Swanson's first time working with cinematographer Steven Goldblatt. She worked with Steven Goldblatt again on Charlie Wilson's War.
In 1989, Swanson joined the cast of Cheers in the recurring role of Kelly Gaines. Her character was a pretty, wealthy, naïve, Lutheran girl, who would eventually marry Woody Boyd, played by Woody Harrelson. She continued to appear in the show until the series ended in 1993.
In 1991, she had a recurring role in the series Baby Talk. In 1992, Swanson appeared on the cover of TV Guide. Swanson modeled in runway show for Ralph Lauren. In 2002, she appeared in an automotive TV commercial in which she was seen driving a GM vehicle to pick up her husband, who emerged from a submarine that popped through thick ice.
Swanson has appeared in a number of other national ad campaigns including commercials for: Broan (directed by Academy Award-winning director Joachim Back), Stacy's Pita Chips (directed by Christian Loubek), Orville Redenbacher (directed by Zach Math), Hummer (directed by Nick Lewin), Ford (directed by Eric Saarinen, son of architect Eero Saarinen and grandson of architect Eliel Saarinen) and Toyota (directed by Jeff Karnoff, and in which she portrayed the wife of Jim Belushi). Swanson also made a public service announcement for the Partnership for a Drug Free America/Anti-Meth Campaign (directed by Michael Patterson).
- Less Than Zero (1987), (uncredited) as Jandie
- Lethal Weapon (1987), as Amanda Hunsaker
- It's Alive III: Island of the Alive (1987), as Tenant
- Slam Dance (1987) (uncredited)
- Almost Grown (1988) Pilot
- Perfect Victims (1988), as Carrie Marks
- The Charmings (1988), as Candy
- She's the Sheriff (1989), as Cherie
- Cheers (1989–1993), as Kelly Gaines/Boyd (24 episodes)
- The People Next Door (1989), as Debbie
- Dragnet (TV Series) (1990), as Miss Carpen
- Baby Talk (1991), as Stella
- The Golden Girls (1992), as Tracy (1 episode)
- Oblivion (1994), as Mattie Chase
- Hope & Gloria (1995), as Sister Theresa
- Oblivion 2: Backlash (1996), as Mattie Chase
- Artie (2000), as Dana Wilson
- NYPD Blue (2001), as Trish Howlett
- Cold Case (2005), as Sarah 1993
- Charlie Wilson's War (2007), as Texas Socialite
- King, Susan (1992-05-09). "For Jackie Swanson of 'Cheers,' the Naive New Bride Is Just an Act". Los Angeles Times. Retrieved 2012-06-09.