Travolta confirmed Preston's death on Instagram and said it followed 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 wrote on Instagram Sunday. "She fought a courageous fight with the love and support of so many. "
He continued: "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, as well as her many friends and loved ones who have been by her side. 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. But please know that I will feel your outpouring of love in the weeks and months ahead as we heal. All my love, JT."
Preston was born on October 13, 1962, in Honolulu, Hawaii. She studied acting at the University of Southern California before starring in the romantic comedy film "Mischief," her first major movie role, according to People magazine.
She went on to star in such hit films as 1988's "Twins," 1996's "Jerry Maguire," and 1999's "For Love of the Game," alongside Kevin Costner.
Preston also had frequent guest-starring roles on TV series like “Medium," “CSI: Cyber” and “Joey.”
Travolta and Preston met while filming 1989′s “The Experts.” They married in 1991 at a midnight ceremony in Paris and had been together ever since.
Her last movie role was portraying Victoria Gotti in the 2018 movie "Gotti." The movie also starred Travolta as John Gotti in the leading role.
Preston's final Instagram post was on Father's Day. The actress shared a picture of her family and wrote: "Happy Father’s Day to the best one I know, we love you."
Preston is survived by her husband, 66, daughter Ella, 20, and 9-year-old son Benjamin. Their son Jett died in 2009 at the age of 16.
The Associated Press contributed to this report