The brains behind more than 30 plays, 20 screenplays and five musicals, Time magazine dubbed him the "patron saint of laughter."
Many of his works are classics of 20th century American theater and Simon has been credited with playing a seminal role -- along with film director Woody Allen -- in re-crafting US humor in the 1960s and 1970s.
His influence has been felt through the generations, The New York Times drawing a line between Simon's early comedies and the character-based comedy in the 1990s hit sitcom "Seinfeld."
Longtime friend Bill Evans announced his death early Sunday in a New York hospital of complications from pneumonia.
His wife, a daughter and grandson were at his bedside, Evans told AFP. He had represented Simon for three decades from 1976 to 2006.
Simon was the author of critically acclaimed and commercial hits such as "Barefoot in the Park" (1963) "The Odd Couple" (1965) "The Sunshine Boys" (1974) and "Lost in Yonkers" (1990).
Much of his work, peppered with witty one-liners, explored the everyday struggles of the middle-classes and inter-family conflict, influenced by his troubled upbringing during the Great Depression.
"The good mechanic knows how to take a car apart; I love to take the human mind apart and see how it works. Behavior is absolutely the most interesting thing I can write about. You put that behavior in conflict and you're in business," Simon told The Paris Review in 1992.
- 'Odd couple' -
"Barefoot in the Park" turned Robert Redford into a star. Redford also appeared in the 1967 hit movie version opposite Jane Fonda.
Other plays that went on to become major Hollywood movies included "The Goodbye Girl" in 1977 that won Richard Dreyfuss an Oscar for best leading actor and "The Odd Couple" in 1968 about two friends sharing an apartment starring Walter Matthau and Jack Lemmon.
"Dilemma is the key word. It is always a dilemma, not a situation," Simon told The Paris Review.
Born on July 4, 1927 in the Bronx, he grew up in northern Manhattan, the son of a skirt-chasing salesman who left the family home multiple times, forcing his mother to rent out her room to make ends meet.
Simon served in the military and then worked with his older brother Danny on producing jokes for television and radio scripts.
"Barefoot in the Park," about a bickering couple inspired by his first marriage, and "The Odd Couple" that followed, were credited with capturing the zeitgeist of the 1960s.
"He was a writer and an artist who couldn't stop going inside of himself and finding new things. Like any creative artist, there was a compulsion to explore and go deeper," Evans told AFP.
"He found a connection in all of us," he added.
"The phrase 'odd couple' is now used in so many different contexts. It was a privilege knowing him."
- 'Americana' -
In the 1960s, at the height of his success, with four plays running on Broadway, Simon was earning about $60,000 a week and easily double that thanks to royalties, The New Yorker reported in 2010.
In the 1980s, he produced the semi-autobiographical trilogy of plays "Brighton Beach Memoirs," "Biloxi Blues" and "Broadway Bound" starring a young Matthew Broderick as the playwright's alter ego Eugene Jerome.
Broderick is now a celebrated stage actor married to film star Sarah Jessica Parker. Evans called the trilogy a "slice of Americana."
Simon described his craft as catharsis.
"It's like analysis without going to the analyst. The play becomes your analysis," he told The Paris Review
In 1991, Simon achieved the highest honor in US drama, winning the Pulitzer Prize for "Lost in Yonkers," an autobiographical comedy about a mother and her daughter that was his last big splash on Broadway.
Such was his wealth that he produced many of his plays and in 1983 he was given the rare accolade of having a New York stage, the Neil Simon Theatre, named in his honor.
In addition to his Pulitzer, he won a Golden Globe and three Tonys. He chalked up 17 Tony nominations and four Oscar nods.
He was married five times to four different women -- he married his third wife twice -- and had three children.