Simon was diagnosed in February 2013 with terminal colon cancer. Yet through it all, he tried to remain upbeat and keep his sense of humor.
"The Museum of Broadcasting called and said, 'We were thinking about doing an archive interview with you. Do you mind if we did it now?' " Simon said with a laugh on Marc Maron's WTF podcast that first ran in May 2013.
During his brief career, the influential Simon also served as the showrunner on the sitcom "Taxi" at the age of 23; wrote for and produced the comedies "Cheers" and "The Drew Carey Show"; and created a Fox series for the legendary stand-up comic George Carlin in the mid-1990s.
Simon also wrote the 1991 film "The Super," a 20th Century Fox comedy starring Joe Pesci as a New York slumlord.
Most recently, Simon was a consultant on the Charlie Sheen series "Anger Management" and hosted a show on Radioio.com. He showed up frequently on Howard Stern's SiriusXM show and in March 2013 thanked the acerbic host for being "the perfect friend."
'His comedy is all about character'
A cartoonist and Stanford graduate, Simon developed "The Simpsons" with Matt Groening (who came up with the characters based on his family) and producer James L. Brooks. All three had worked on "The Tracey Ullman Show," where Bart Simpson and his family got their start as animated sketches shown before and after commercials.
"The Simpsons," centering on TV's "first fully self-aware dysfunctional family," as Simon put it, debuted on Fox on December 17, 1989, and is now the longest-running primetime series in American history.
Ken Levine, an Emmy winner who has written for "The Simpsons" and other sitcoms, described Simon's contribution to the show during a 2009 interview published in Stanford Magazine.
"Sam brought a level of honesty to the characters," Levine said. "Is it too bizarre to say he made cartoon characters three-dimensional? His comedy is all about character, not just a string of gags. In 'The Simpsons,' the characters are motivated by their emotions and their foibles. 'What are they thinking?' -- that is Sam's contribution. The stories come from the characters."
Simon also is credited with assembling the show's elite writing team that included Al Jean, George Meyer, John Swartzwelder, Mike Reiss, Jon Vitti and Conan O'Brien.
"I remember Sam coming into the room, and me pitching to him and initially being really intimidated," O'Brien told Vanity Fair in 2007. "He's hilarious. It was fun to try and make him laugh. I remember that about Sam. If I could make Sam laugh, I was excited."
Tired of the grind, Simon exited the show in 1993 after four seasons but worked out a deal tied to home video sales that he said paid him "tens of millions" every year. The agreement also guaranteed him executive producer credit long after he departed, and his name appears in the credits of every episode.
A couple of years after he left, Simon knew he would have enough money to retire from show business. He was in his mid-30s.
Praise 'like Tom Sawyer's funeral'
As detailed in The Hollywood Reporter's 2013 Philantrophy Issue, Simon's charitable contributions include founding the Malibu-based Sam Simon Foundation (worth nearly $23 million as of 2011) that rescues the hungry and feeds stray dogs.
His other pet charities include PETA, which in February thanked him for his support by naming its Norfolk, Virginia, headquarters The Sam Simon Center; international nonprofit Save the Children; and the Sea Shepherd Conservation Society, a global marine conservation organization. His generosity led the latter in 2012 to name one of the four ships in its fleet of vessels -- used to hinder whaling and illegal fishing -- the M/Y Simon.
Simon also turned a Malibu spread into a canine haven that rescues dogs from kill shelters and trains them as companions for the deaf.
"The sort of lifetime achievement stuff that I'm getting now is kind of like Tom Sawyer's funeral because they all know I'm sick," Simon told THR's Gary Baum. "I am getting buildings named after me and awards and stuff. The truth is, I have more money than I'm interested in spending. Everyone in my family is taken care of. And I enjoy this."
In May 2014, it was revealed that Simon spent $60,000 to rescue an abused thoroughbred.
Simon, who won eight of his Emmys for writing/producing "The Simpsons" (many after he left) and one for producing "The Tracey Ullman Show," was married to and divorced from actress Jennifer Tilly (1984 to 1991) and Playboy Playmate Jami Ferrell (for mere weeks in 2000). Neither marriage produced any children.
Across the street from Groucho
Born June 6, 1955, Simon grew up in Beverly Hills in an era when the neighborhood was "quaint," as he put it. Groucho Marx lived across the street, and he recalled walking into his parents' room as a youngster and finding the legendary comic and his mom sitting on the bed. (He stressed they weren't about to have sex.) Another time, Elvis Presley returned the dog that Simon had lost.
While at Stanford, Simon drew cartoons for the local newspapers in San Francisco and the school paper and landed a job at Filmation Studios doing storyboards for "The New Adventures of Mickey Mouse" and "Heckle & Jeckle."
Simon scored his first TV writing gig on the animated "Fat Albert and the Cosby Kids" in 1979. He mailed in a script to "Taxi" (co-created by Brooks) that was accepted, and that led to a staff writing position and then the job as showrunner.
Simon also went on to direct episodes of the Carlin show, "The Drew Carey Show," "Friends," "Norm" and "Anger Management."
An avid poker player, Simon re-created his home game in a penthouse at the Palms Hotel in Las Vegas for a Playboy TV show in 2009. The show also featured Tilly -- a very good player -- as well as comedians Dave Attell, Norm Macdonald, Jeffrey Ross and Artie Lange.
Another one of Simon's more eclectic pursuits was working the corner at amateur fights and serving as president of Sweet Science Inc., which managed boxer Lamon Brewster. His fighter stunningly knocked out Wladimir Klitschko to win a share of the heavyweight championship in 2004.
During his chat with Maron, Simon noted that the way to know when to put down your ailing dog is to "list the three things he loves to do. When he can't do those any longer, it's time.
"One of my three things is laying in bed and watching TV. So by that criteria, I will never be euthanized."
Later, talking about all the millions he's given to charity, he added: "I kinda like it when people talk about me as a special person. But I know I would be a nut if I didn't have a lot of money."