The Beverly Hills 90210 and Riverdale star never recovered after being rushed to hospital on Wednesday.
He passed away this morning at St. Joseph's Hospital in Burbank surrounded by his family - including Jack and Sophie and fiance Wendy Madison Bauer.
His rep said: "Actor Luke Perry, 52, passed away today after suffering a massive stroke.
"The family appreciates the outpouring of support and prayers that have been extended to Luke from around the world, and respectfully request privacy in this time of great mourning.
"No further details will be released at this time."
Luke had been sedated to allow his brain to recover but the damage was too extensive, TMZ reports.
The US actor first shot to fame in the '90s, playing Dylan McKay in popular TV series Beverly Hills, 90210.
However, most recently Luke has found prominence playing Archie's dad Fred Andrews in hit show Riverdale, and the star was only recently spotted filming scenes on the Warner Brothers Hollywood lot.
He had also shot a role in Quentin Tarantino's upcoming Charles Manson film Once Upon a Time in Hollywood.
On the same day that Luke suffered his stroke, Fox announced that they are rebooting Beverly Hills, 90210.
The star was yet to sign on to the project, despite his former costars - including Tori Spelling, Jennie Garth, and Brian Austin Green - already being confirmed.
Luke is father to two children, 22-year-old Jack, and 18-year-old Sophie, who he shares with his ex-wife Rachel Sharp.