The actor was found dead at his home in his Los Angeles, law enforcement sources told US media.
Friends, which followed the fortunes of six young friends living in New York City, aired from 1994 until 2004.
Its final episode was watched by 52.5 million in the US, making it the most watched TV episode of the 2000s.
The LA Times and TMZ, which first reported that Perry had died, said the actor was found unresponsive in a hot tub at his house.
A Los Angeles Fire Department spokesperson told the BBC that first responders went to an address in the Pacific Palisades area, regarding a "water emergency" of an unknown type, but did not name Perry.
Warner Bros TV, which produced Friends, said "we are devastated by the passing of our dear friend Matthew Perry".
"Matthew was an incredibly gifted actor and an indelible part of the Warner Bros. Television Group family," the statement read.
"The impact of his comedic genius was felt around the world, and his legacy will live on in the hearts of so many. This is a heartbreaking day, and we send our love to his family, his loved ones, and all of his devoted fans."
Courteney Cox, Jennifer Aniston and Matthew Perry in a scene from Friends
Born in Massachusetts in 1969, Perry was raised in Ottawa, Canada, where he attended elementary school with Justin Trudeau, who later became Canadian prime minister.
Perry moved to Los Angeles as a teenager. He starred as Chazz Russell in Boys Will Be Boys and also had roles in shows including Growing Pains.
But he became an international star on Friends, a show which followed the lives of six New Yorkers navigating dating, careers and friendship.
The comedy, co-starring Jennifer Aniston, Courteney Cox, David Schwimmer, Matt LeBlanc and Lisa Kudrow, became one of the most successful shows of all time.
Perry was cast as the awkward Chandler Bing, famous for his sarcastic one-liners. The role earned him a Primetime Emmy nomination in 2002.
Perry (far left) with the other stars of Friends in 1997
Perry battled for years with addiction to painkillers and alcohol, and attended rehabilitation clinics on multiple occasions.
In 2016, he told BBC Radio 2 that he could not remember three years of filming during Friends, because of drink and drugs.
In an interview last year, he spoke about how he did not watch the show.
"I didn't watch the show, and haven't watched the show, because I could go, 'Drinking, opiates, drinking, cocaine,'" he said. "I could tell season by season, by how I looked. That's why I don't wanna watch it, because that's what I see.
"Bit I think I'm going to start to watch it because it's been an incredible thing to watch it touch the hearts of different generations."
Perry also appeared in several films, including Fools Rush In, Almost Heroes and the Whole Nine Yards.
Maggie Wheeler, who played Janice in Friends, was the first of Perry's co-stars to publicly pay tribute to the actor.
Ms Wheeler said the joy Perry brought to "so many" in his "too short lifetime will live on".
"I feel so very blessed by every creative moment we shared," she wrote on Instagram.
Cruel Intentions actress Selma Blair said Perry was her "oldest boy friend", adding: "All of us loved Matthew Perry, and I did especially. Every day. I loved him unconditionally. And he me.
"And I'm broken. Broken hearted. Sweet dreams Matty. Sweet dreams."
By George Wright
BBC News