A Washington native, Hupp appeared in Seattle theater productions before landing her first film role, a one-line part in the coming-of-age drama "Vision Quest (1985)". This led to a move to Los Angeles, where the actress took guest roles on episodes of the series "Scarecrow and Mrs. King (1983)" and "My Sister Sam (1986)". A featured part in the "Disney Sunday Movie" presentation "Splash, Too (1988)" followed.

 Jana Marie Hupp racked up more TV series guest credits, with appearances in episodes of "Who's the Boss? (1984)", "Empty Nest (1988)", Star Trek: The Next Generation, "Knots Landing (1979)", "A Different World (1987)", "Melrose Place (1992)", and "Camp Wilder (1992)". These frequent appearances and a small but impressive turn as the USO girl who shares a dance with "Barton Fink" in the film (1991) made Hupp a fairly recognizable performer despite her lack of starring roles. She would reach a wider audience with a memorable role as the woman for whom George (Jason Alexander) considers religiously converting on "Seinfeld (1990)". The following year the actress made her TV series regular debut on the short-lived risque sitcom "Wild Oats (1994)", playing a hairdresser with bad taste in men. Hupp rebounded with a regular role as a sharp police sergeant in "Public Morals (1996)", a sitcom that suffered a similarly quick demise. Sandwiched between these two series was her cameo role as a scientist in the summer blockbuster "Independence Day (1996)".

The gritty police drama "Brooklyn South (1997)" offered the actress a challenge, portraying the troubled wife of a police officer (Titus Welliver). Guest roles in "Nash Bridges (1996)" and "The Drew Carey Show (1995)" followed, and she had a memorable guest role on "Providence (1999)" as a woman who elects to have radical preventative surgery in order to avoid the trauma of breast cancer that has plagued her family. She teamed up with fellow "Providence" guest star Tom Cavanagh on "Ed", a quirky hour-long comedy-drama series chronicling a New York City lawyer's return to his small hometown. Hupp played Nancy Burton, a successful career woman returning to work after the birth of her child who is plagued by guilt and worries that the baby will forget her in the hours she is away from home. Hupp proved a strong addition to the cast, and had a comfortable chemistry with onscreen husband Josh Randall. Sure to last longer than her other series outings, "Ed" could serve as the vehicle for Hupp's latter-day breakthrough.