Travolta confirmed his wife's death in an Instagram post late Sunday. He said she died after a two-year battle with breast cancer.
"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 said of his wife of 28 years. "She fought a courageous fight with the love and support of so many."
The "Grease" star went on to say he and his family "will forever be grateful to her doctors and nurses at MD Anderson Cancer Center, all the medical centers that have helped, as well as her many friends and loved ones who have been by her side."
Preston had a lengthy career on film and television and at times appearing in films with her husband. They had three children together.
WATCH: Kelly Preston remembered
Preston and Travolta were married at a midnight ceremony in Paris in 1991 while the couple were expecting their first son, Jett.
In January 2009, Jett Travolta, 16, died after a seizure at the family's vacation home in the Bahamas. The death touched off a court case after an ambulance driver and his attorney were accused of trying to extort $25 million from the actors. The two allegedly threatened to release sensitive information about their son's death.
Travolta testified during a criminal trial that ended in a mistrial and was prepared to testify a second time, but decided to stop pursuing the case. He cited the severe strain the case and his son's death had caused the family.
Both Preston and Travolta returned to acting, with Preston's first role back in the Nicholas Sparks adaptation, "The Last Song," which starred Miley Cyrus and her future husband, Liam Hemsworth.
They had two other children, daughter Ella Bleu in 2000 and son Benjamin in 2010.
Travolta and Preston met while filming 1988's "The Experts."
They last starred together in the 2018 film "Gotti," with Travolta playing John Gotti and Preston playing the crime boss's wife, Victoria.
Preston's death was first reported by People magazine.