An innovative and eccentric humorist with pillowy lips and a voice that always seemed on the verge of a whine, Shandling claimed to disdain too much logic cluttering his life.
"The answer isn't gonna be in the facts," he told The Associated Press in 2009. "It's gonna be in intuition. That's how I work creatively. I'm always teaching people that the answer to that creative question is right here, in the room, between us here."
More to the point, it was dealing with the questions he confronted in himself.
Born on Nov. 29, 1949 in Chicago, Shandling was raised in Tucson, Arizona. On arriving in Los Angeles as a young adult, it was a short hop from a brief stint in the advertising business to comedy writing and stand-up.
Then in the 1980s, he began to experiment with TV comedy, and to toy with the sitcom form, with his first series, It's Garry Shandling's Show, a Showtime project that made no bones about its inherently artificial nature: The actors in this otherwise standard domestic comedy routinely broke the fourth wall to comment on what they were up to. Even the theme song began with the explanatory lyrics, "The theme to Garry's show...."
In 1992, he created his comic masterpiece with The Larry Sanders Show, which starred him as an egomaniacal late-night TV host with an anxiety-ridden show-biz life behind the scenes. The show help start the careers of Judd Apatow (Freaks and Geeks, 40-Year-Old Virgin) Jeffrey Tambor (Arrested Development, Transparent) and Jeremy Piven (Entourage).
It was just three months after Johnny Carson had retired from "The Tonight Show," where Shandling had appeared as a stand-up and occasional Carson stand-in. It seemed a wry but deeply felt homage to the King of Late Night.
But it was more. "Larry Sanders" proved to be an act of courage, a brave effort led by someone portraying a character dangerously close to himself. As Larry, Garry dug deep to confront his own demons, and did it brilliantly as the series teetered between dual realities: public and private; make-believe and painfully true.
Real-life celebrities appeared as guests on Larry's show-within-the-show, and also interacted with him "off the air."
David Duchovny, agreeing to come on the show, also came on to Larry romantically once he got the chance.
Jim Carrey delivered a rip-roaring comic tribute to his host on the final broadcast, then, during a commercial break, turned on him in rage over a long-ago slight.
"Are you doing a bit, now?" asked Larry, perplexed.
"We're OFF the air," Carrey hissed. "This is real life now."
The show explored the fuzzy distinction between TV life and real life, and the loneliness of someone at its crossing. The closest thing Larry had to friends were his chronically needy announcer Hank (Jeffrey Tambor) and his Napoleonic producer, Artie (Rip Torn). Together the three actors were among TV's best-ever trios.
"Garry was my dear friend and was and always will be my teacher," Tambor wrote in a statement. "Garry redesigned the wheel of comedy and he was the kindest and funniest of Geniuses. I will miss him so much."
Torn also expressed deep sadness about Shandling's death. "Working with him was one of the great privileges of my career," he wrote. "He was a comic talent of immense originality who enthusiastically encouraged and responded to the originality of others."
After "Sanders" ended in 1998, Shandling's public appearances were few.
He was mentioned as a candidate to follow David Letterman as a bona fide late-night host for CBS' 12:30 a.m. slot, but no deal was made.
"I would not do a show where you just sit and talk to somebody," Shandling had said back in 1993 when he was courted by NBC to take over for Letterman on "Late Night."
His films included "Hurlyburly" in 1998, "What Planet Are You From?" in 2000 and "Zoolander" in 2001.
He hosted the Emmy Awards in 2000 and 2004.
On the latter occasion, he spotted Donald Trump in the audience and congratulated the billionaire developer for hosting the Emmy-nominated "The Apprentice."
"Nice to see a man who's paid his dues, worked hard," Shandling said. "We all know what it feels like to have to build 80-story condos and gambling casinos just to get our foot in the door in show business."
Jamie Masada, owner of comedy club the Laugh Factory, said he met with Shandling a few weeks ago and the comedian didn't appear to have any health problems.
"He looked healthy as could be," Masada said.
"Garry Shandling, besides being a comedian, I always said he was a doctor of soul. He had a lot of kindness in him. He was a very generous person," Masada said.
In his own business dealings, Shandling became one of the rich and famous targeted by private eye Anthony Pellicano, who was sentenced to prison in 2008 on convictions of racketeering and more than six dozen other counts, including conspiracy, wire fraud and wiretapping in the Hollywood wiretaps case.
Pellicano was accused of wiretapping stars such as Sylvester Stallone and bribing police officers to run names of people, including Shandling, through law enforcement databases.
While Shandling never married, his most public romance was with "Sanders" co-star and fiancee Linda Doucett, who played Hank's comely assistant in the series' early seasons.
Doucett sued Shandling after he fired her following their breakup in the mid-1990s, receiving a reported $1 million settlement, The New York Times reported in 2006.
Several comedians expressed their remorse and respect for Shandling on Social Media.