He was 59.
Simon died yesterday at his home in Los Angeles, his foundation, the Sam Simon Foundation, confirmed the news via Facebook, reported Time.
"It is with much sadness that we must let you know that Sam Simon has passed over," the announcement read.
Simon was diagnosed with colon cancer in 2012, and was told he had only three to six months left to live. He survived that diagnosis.
Simon had said in an interview earlier that he was able to stay positive despite his diagnosis.
He reportedly said he was planning to donate $100 million of his fortune to charity, mostly to animal organisations.
A graduate of Stanford University, the director had nine primetime Emmys to his name.
One was for his work on The Tracey Ullman Show, where fellow Simpsons co-creators Matt Groening and James L Brooks also worked, while the other awards were for The Simpsons.
Simon left the show in 1993, just four years after it debuted on Fox, but remained in the credits as an executive producer and continued to earn money from the show thanks to home
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