George Clooney is speaking out publicly about the death of Matthew Perry ... saying the actor wasn't happy on the set of his hit sitcom, "Friends."

Clooney sat for an interview published Tuesday in Deadline to promote his new film, "The Boys In the Boat," -- and he opened up about his relationship with Perry dating back to the '90s when they first met and played paddle ball together.

At the time, Perry was 16 and searching for success, desperately trying to get on a sitcom. Clooney described Perry as a "great, funny, funny, funny kid."

One day, Clooney said he was chatting with Perry, who told him, "I just want to get on a regular sitcom and I would be the happiest man on earth."

Perry got his wish, scoring a leading role as Chandler Bing on "Friends," which Clooney noted was "probably one of the best ever" TV shows.

Yet, Perry still wasn’t happy, Clooney said, because it "didn’t bring him joy or happiness or peace."

Back then, the two stars worked on the Warner Brothers lot next to each other -- and Clooney recalled it was "hard to watch" Perry because "we didn't know what was going through him."

Clooney insisted he had no idea Perry was popping 12 Vicodin a day and "all the stuff he talked about, all that heartbreaking stuff."

Clooney added that money and success do not automatically translate into happiness, explaining, "You have to be happy with yourself and your life."

As you know ... Perry died of "the acute effects of ketamine," a drug used to treat depression and is sometimes taken recreationally. The L.A. Coroner found several contributing factors: drowning, coronary artery disease, and buprenorphine effects. Buprenorphine is used to ween addicts off opioids.