However, while nowhere near as successful as his TV roles, the actor's film career had its own share of gems.
Many of his movie roles had Chandler-style flair, but they also gave Perry a chance to present himself as an appealing leading man.
In chronological order, here are five of Perry’s best film performances.
1. A Night in the Life of Jimmy Reardon (1988)
Credited as Matthew L Perry, the actor made his film debut in this underappreciated teen comedy starring River Phoenix in the title role.
Playing the role of Jimmy's best friend, Fred Roberts, an uptight teen from the suburbs, Perry showcases some of the deft comic timing he would bring to his role of Chandler in Friends six years later.
While A Night in the Life of Jimmy Reardon tanked at the US box office, the film has been reappraised by a new generation of critics who praised its charm and offbeat humour.
2. Fools Rush In (1997)
This was Perry's first lead film role.
Fresh from his success in Friends, Perry attempted to channel some of his character's manic energy into this romantic comedy with Salma Hayek.
Playing strait-laced construction manager Alex, he meets and falls in love with the free-spirited Mexican-American photographer Isabel (Hayek), resulting in an unexpected pregnancy. Clashes of culture and in-laws ensue, ultimately making Fools Rush In an immensely watchable comedy film.
3. The Whole Nine Yards (2000)
It is fair to say that for the majority of his career, Perry’s film roles often echoed his work as Chandler in Friends.
While it yielded clunkers like 1998's Almost Heroes and 1999’s Three to Tango, Perry had a critical and commercial hit with The Whole Nine Yards.
The black comedy tells the story of a suburban dentist sucked into the criminal underworld after realising his neighbour (Bruce Willis) is a hitman.
While the set-up feels like a rip off the far superior Analyze This, released a year prior with Robert De Niro and Billy Crystal, The Whole Nine Yards is fun enough due to Perry and Willis's peppy chemistry.
4. Numb (2007)
Partly inspired by filmmaker Harris Goldberg's personal experiences, Perry plays screenwriter Hudson Millbank in Numb, who is newly diagnosed with depersonalisation disorder.
With the support of his psychiatrist, friends and love interest (Lynn Collins), Hudson gets to grips with his condition and finds fresh meaning to his existence.
5. 17 Again (2009)
Perry's last film role finds him going back to the teen genre that gave him his start, albeit with a dash of fantasy in the mix.
Perry plays Mike O'Donnell, a failed husband and athlete.
After a chance encounter with a mystical guru in the guise of a janitor, he is transported back to his 17-year-old self (Zac Efron) and tries to take some of life's opportunities once spurned.
A box office hit, 17 Again proved Perry had lost none of his Friends appeal, five years after the show wrapped.