She had been battling breast cancer within 2 years, John said, and "fought a courageous fight with the love and help of so many.
In an identical with community, a family representative said that Preston died on Sunday morning.
The actress had not been photographed publicly at a major event since June 2018 when she walked the red carpet with her husband for the premiere of his film "Gotti" in which he portrayed the late mobster, John Gotti and she played his wife, Victoria Gotti.
Born Kelly Kamalelehua Smith in Honolulu, Preston studied acting at the University of Southern California before landing some bit parts on television including "CHiPs" and "Roseanne."
That led to the role of playing Mary Lee on the short-lived television series "For Love and Honor."
But Hollywood took notice in 1988 when she starred as Marnie Mason, Arnold Schwarzenegger's character's love interest in the comedy "Twins," a film which also co-starred Danny DeVito.
That same year she met Travolta during a screen test for the film "The Experts."
During a 2018 interview on "Live with Kelly and Ryan," Preston talked of how she and Travolta eloped to Paris in 1991 after their wedding plans in New York City became unmanageable.
She said they discovered they had to be residents of Paris for the marriage to be legal and so they also married stateside.
She had previously been married to actor Kevin Gage from 1985 to 1987 and had high profile romances with George Clooney and Charlie Sheen (to whom she was briefly engaged) before she wed Travolta.
Preston also starred in the 90's classics like "Jerry Maguire" and "For Love of the Game."
In 1992 she and Travolta welcomed their first child, son Jett, who died in 2009 following a seizure, while the family vacationed in the Bahamas.
Daughter Ella followed in 2000 and son Benjamin who was born in 2010.
Preston told Health magazine she was going to become a mom again at 48 and said she and Travolta had been trying off and on to conceive.
"When I found out I was pregnant, I was floored," People magazine reported her as telling Health.
She acted less in the years that followed Benjamin's birth, most notably in a guest-starring role on the TV series "CSI: Cyber" and the film "Gotti" with her husband.
Preston and Travolta have been two of the highest-profile members of the Church of Scientology and last year US Weekly reported that the couple talked to the publication about their marriage, the loss of Jett, and how the church had helped them cope.
"The church never left our sides for two years," Travolta reportedly said.
Preston and Travolta's daughter, Ella Travolta, posted a tribute to her mother on Instagram.
John Travolta ended his post by saying, "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.