The television producer and noted animal rights activist was 59.
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"It is with much sadness that we must let you know that Sam Simon has passed over," a Facebook post for The Sam Simon Foundation said Monday.
Simon, who was diagnosed with terminal cancer in 2012, donated millions of dollars to the animal rights group PETA, on whose executive committee he served.
Simon began his career in television in the late 1970s after taking a job animating Saturday morning cartoon shows after college. He was encouraged to send a draft script to the sitcom Taxi, after which he went to work for the show.
He subsequently worked on Cheers, It's Garry Shandling's Show, and The Tracey Ullman Show, where he first encountered short clips featuring an animated yellow family called the Simpsons.
He earned his fortune after co-creating the popular animated television show for Fox in 1989, along with Matt Groening and James L. Brooks.
Frazier Moore / AP
He served as executive producer and showrunner for the show's first two seasons, assembling its initial team of writers.
"In the beginning, I was skeptical it could be successful, but I was not skeptical it could be good," he told his alma mater, Stanford University, in 2011. "I was hoping for 13 episodes that my friends would like. It's a good lesson, isn't it? If you do something trying to make your friends laugh and that you can be proud of, you can also be successful."
"Time called it the best TV series of the 20th century," Simon said. "There weren't any TV series in the 19th century, so I assume that makes it the best of all time."
After falling out with Groening and Brooks, Simon left the show in 1993, but negotiated a deal that saw him still listed as a producer and earned him millions of dollars a year from the show's continued success.
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