The tragic news is another brutal blow for the Hollywood actor, who is still grieving over the death of his late wife, Kelly Preston, who died in July.
According to People magazine, the American actress had been battling breast cancer for the last two years.
A spokesperson for the family confirmed the news to the American publication, saying the family had chosen to keep her fight private.
"Choosing to keep her fight private, she had been undergoing medical treatment for some time, supported by her closest family and friends," the representative said.
"She was a bright, beautiful and loving soul who cared deeply about others and who brought life to everything she touched.
“Her family asks for your understanding of their need for privacy at this time," they added.
Husband John later posted an emotional tribute on his Instagram account.
“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,” John began.
“She fought a courageous fight with the love and support of so many. 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,” he concluded.
Prior to Kelly's death, John's greatest tragedy was losing his 16-year-old son Jett, who died in 2009 after suffering a seizure at their vacation home in the Bahamas.