A source close to Van Halen told PEOPLE that the guitar hero had a rapid decline in health over the past three days and that the cancer had "spread to all his organs."
His wife Janie Liszewski, son Wolf and ex-wife Valerie were by his side at the time of his death.
Earlier this year, his former bandmate David Lee Roth told Las Vegas-Review Journal that Van Halen was not doing well.
The iconic guitarist had battled cancer for more than 10 years, according to TMZ. He previously defeated tongue cancer in 2002 after a two-year battle.
Last year, he was admitted to the hospital with intestinal issues after a bad reaction to his cancer treatment.