The American Crime Story star took to Instagram to share the sad news with a heartbreaking post memorializing the actress and her life.
"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. "She fought a courageous fight with the love and support of so many."
The actor shared his gratitude for all those who did their best to help Preston fight her ailment over the past two years.
"My family and I will forever be grateful to her doctors and nurses at MD Anderson Cancer Center, all the medical centers that have helped," he wrote, "as well as her many friends and loved ones who have been by her side."
Travolta honored his wife, sharing, "Kelly’s love and life will always be remembered."
"I will be taking some time to be there for my children who have lost their mother, so forgive me in advance if you don’t hear from us for a while," he concluded. "But please know that I will feel your outpouring of love in the weeks and months ahead as we heal."
Travolta and Preston met in 1987 on the set of the comedy The Experts, and went on to tie the knot in September 1991.
The pair shared three children -- 20-year-old daughter Ella and 9-year-old son Benjamin, and their son, Jett, who died in 2009 at the age of 16.
Preston appeared in dozens of films and TV shows, and frequently acted in roles opposite her husband. Her most recent big screen appearance came in the 2018 mob biopic Gotti, in which she starred as Victoria Gotti, wife of crime boss John Gotti, as portrayed by Travolta.