Sam Simon, who was one of the major creative forces behind “The Simpsons” and who left the show after its fourth season in a lucrative arrangement that allowed him to spend much of the rest of his life giving his money away, died on Sunday at his home in the Pacific Palisades area of Los Angeles. He was 59.

His death was confirmed by his agent, Andy Patman. Mr. Simon learned a few years ago that he had colon cancer.

The cartoonist Matt Groening, recruited by the producer James L. Brooks, invented the Simpson family for a series of short animated segments first seen on “The Tracey Ullman Show” in 1987. Mr. Groening named some of the characters after members of his own family, including Homer and Marge, the parents.

Although Mr. Groening is the person most closely associated with “The Simpsons,” Mr. Simon — who had published cartoons while he was a student at Stanford, worked on the cartoon show “Fat Albert and the Cosby Kids” and been a writer and producer for the sitcoms “Cheers” and “Taxi” — played a crucial role as “The Simpsons” evolved into a half-hour series. It became the longest-running sitcom in television history.

Mr. Simon helped populate Springfield, the fictional town where the Simpsons live, with a range of characters. He insisted that the show be created using some conventional sitcom techniques like having the writers work collectively. He had the voice actors read their parts as an ensemble, with the goal of giving the show more lifelike rhythm and timing. And he hired many of the show’s first writers, a number of whom gave him credit for informing its multilayered sensibility, one that skewers pieties with anarchic humor and sometimes vulgarity while celebrating family and community.

“If you leave out Sam Simon, you’re telling the managed version,” Jon Vitti, one of the show’s first writers, told The New York Times in 2001. “He was the guy we wrote for.”

Jay Kogen, a former producer of “The Simpsons,” told The Times that Mr. Simon “knew the freedom that animation provides and utilized it to the full extent.”

Mr. Groening, who was best known before “The Simpsons” for creating the syndicated comic strip “Life in Hell,” drew attention for his unusual career move into television animation. But Mr. Simon also had to change directions: He had to figure out how to make an unconventional product appeal to the mainstream audiences he had reached on “Taxi” and “Cheers.” He was surprised at how well it worked.

“There would be a few minutes where you’d have a parody of a Kubrick movie, and then you’d have Homer on the kitchen counter eating cake like a dog,” he told Stanford Magazine, a university publication, in 2009. “I thought some people would like some aspects of it, but I wasn’t sure how many would come along for the full ride. It turned out I was incredibly wrong. Homer is now the prototype for every male lead on a comedy show.”

Mr. Simon’s work on the show is also remembered for the way it ended. He and Mr. Groening clashed frequently — Mr. Groening was among several people, including Mr. Simon himself, who said that Mr. Simon could be difficult to work with — and Mr. Simon left in 1993, after four seasons.

It was not an amicable split, but it was extraordinarily profitable for Mr. Simon. He retained the title of executive producer and was given royalties from future home video sales. As “The Simpsons” moved into syndication and lucrative VHS and then DVD sales, it made Mr. Simon wealthy long after he was no longer directly involved in the show. He said in interviews that it provided him with “tens of millions” of dollars each year.

Mr. Simon angered Mr. Groening early on by expressing skepticism about the show’s prospects, suggesting that it would last only one season. But he later emphasized how fortunate he was to have been part of it. Not that he caught every episode after he left.

“If I had to watch it to cash my checks,” he said, “I would.”

Mr. Simon put his money toward his passions. He started a foundation that trained dogs to help disabled people, including veterans of the wars in Iraq and Afghanistan, and he gave generously to the Sea Shepherd Conservation Society and People for the Ethical Treatment of Animals, among other groups. PETA’s headquarters in Norfolk, Va., was renamed the Sam Simon Center in 2013.

After Mr. Simon learned he had cancer, he announced his intention to give nearly all his “Simpsons” royalties to charity. “I’ve given most of it away,” he said in 2013 when asked about his wealth on the comedian Marc Maron’s podcast. “I won’t be rich again until we get our quarterly installment from ‘The Simpsons.’ ”

Mr. Simon was born on June 6, 1955, in the Los Angeles area, to Arthur and Joan Simon. His father owned a company that made discount clothing, his mother owned an art gallery, and Mr. Simon grew up comfortably in Beverly Hills, across the street from Groucho Marx and around the corner from Priscilla Presley.

He was recruited to play football at Stanford but quit after one day of practice. While he was a student there, he drew sports cartoons for The San Francisco Chronicle. He graduated in 1977.

Four years later, after he had worked as a storyboard artist and writer for Filmation Studios, he mailed an unsolicited script to the producers of “Taxi.” They accepted and produced his script, and by the following year, Mr. Simon had become one of the show’s main writers. He was soon writing and producing for several other shows, including “Cheers.”

After he left “The Simpsons,” Mr. Simon helped develop other series, including the short-lived program “The George Carlin Show” and the “The Drew Carey Show,” which enjoyed a long run. He also became a competitive poker player and hosted a program on Playboy TV featuring celebrities playing Texas hold ’em. He was a frequent guest on Howard Stern’s radio show. He was recently a consultant on the Charlie Sheen sitcom “Anger Management.”

In 1997, he entered a different arena entirely when he began managing the boxer Lamon Brewster. In 2004, Mr. Brewster won the World Boxing Organization heavyweight championship.

Mr. Simon’s marriage to the actress and competitive poker player Jennifer Tilly ended in divorce, but the two remained close. A brief marriage to Jami Ferrell, a Playboy model, also ended in divorce. Information about survivors was not immediately available.

One beneficiary of his philanthropy, the Sea Shepherd Society, which opposes whale hunting, named one of its boats for Mr. Simon. (Others are also named for celebrity supporters.) In 2011, his Sam Simon Foundation started a program that provides low-income families with free vegan meals.

Asked whether he was imposing his own vegan diet on those his charity served, Mr. Simon said: “They can eat all the meat they want. I’m just not going to pay for it.”