Shandling was known for "breaking the fourth wall" - speaking directly to the audience - in his show, which aired from 1986 to 1990.
He starred in the critically acclaimed Larry Sanders Show from 1992 to 1998.
His self-aware brand of comedy, which relentlessly mocked the artificial nature of show business, is credited with influencing other hit shows like Tina Fey`s 30 Rock and Larry David`s Curb Your Enthusiasm.
Born in Chicago in 1949, Shandling got his start in Hollywood as a sitcom writer for shows such as Sanford and Son and Welcome Back, Kotter.
A popular stand-up comedian, Shandling often appeared on the Tonight Show with Johnny Carson during the 1980s.
He was in the running to replace Carson when the chat show host retired.
Shandling was a frequent awards show host - emceeing both the Grammy and Emmy awards for several years.
Actor Steve Martin wrote on Thursday that Shandling would offer suggestions when Martin would host the Academy Awards.
Shandling most recently starred as a villainous senator in Iron Man 2 and Captain America: The Winter Soldier.
Fellow comedians Amy Schumer and Ricky Gervais were among the many rushing to pay tribute to Shandling.
"Goodbye Gary Shandling thank you for your kindness and your generosity and for making me laugh so damn much," said Shumer.
Gervais wrote: "RIP the great Garry Shandling. Surely, one of the most influential comedians of a generation."
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