"It is with a very heavy heart that I inform you that my beautiful wife, Kelly, has lost her two-year battle with breast cancer," Travolta wrote Sunday in an Instagram post. "She fought a courageous fight with the love and support of so many."
The actor praised doctors and nurses at MD Anderson Cancer Center in Houston as well as Preston's "many friends and loved ones who have been by her side."
"Kelly's love and life will always be remembered," he added.
Born Kelly Kamalelehua Smith in Honolulu, Preston landed her first major movie role in 1985 in the teen comedy Mischief. She went on to star in 1980s hits such as SpaceCamp (1986) and Twins (1988) before marrying Travolta in 1991.
Preston's career also included roles in such notable films as Jerry Maguire (1996) with Tom Cruise, From Dusk Till Dawn (1996) with George Clooney, Addicted to Love (1997) with Meg Ryan and For Love of the Game (1999) with Kevin Costner. Her final film role was playing opposite her husband of 28 years in the 2018 film Gotti.
Preston and Travolta had three children together. Their first child, Jett, died in 2009 at age 16.
Preston is survived by her husband, daughter Ella, 20, and 9-year-old son Benjamin.