Brenner, who had been fighting cancer, died peacefully at his home in New York City with his family at his side, according to Jeff Abraham, his friend and publicist.
The lanky, always sharply dressed Brenner became one of the most frequent visitors to Johnny Carson's Tonight in the 1970s and '80s.
His 150-plus appearances as guest and substitute host turned the former documentary filmmaker into a hot comedian, one who was ubiquitous on other talk shows and game shows.
He also briefly hosted his own syndicated talk show in 1987 and starred in four HBO specials.
Fresh StartDecades ago, Brenner, who was raised in working-class south Philadelphia and graduated with honors from Temple University, had burned out on filmmaking – "You don't change the world by doing documentaries," he told CBS Sunday Morning in 2013 – and decided to give comedy a try. He was on the verge of quitting when his effort to impress talent bookers at Tonight worked.
His career soared after his first appearance in January 1971. He went from being nearly broke to overwhelmed by a then-hefty $10,000 in job offers the day after he was on the show.
"I never thought this was going to turn my life upside down and give me my whole future," he told Sunday Morning.
He also recalled how hard Carson made him work on Tonight, asking Brenner to do a monologue each time he appeared. Other veteran comics headed straight for the couch to banter with the host.
Carson's explanation was "I like to sit back, smoke a cigarette and laugh for six minutes," Brenner recalled.
Brenner took a brief stabs at TV fame, with the 1976 sitcom Snip and the talk show Nightlife he hosted in 1987, and saw Jay Leno follow Carson as Tonight host.
In a 1995 interview with the AP, Brenner imagined a different path with Tonight.
"I really believe that had ... Johnny Carson retired in the early '80s, then I would be sitting behind that desk," he said. "I don't think there's any doubt."
Family FirstBrenner's take on his career path, as he described it in a 2000 interview with The Associated Press, was that he put family before stardom.
He said a long custody battle with a girlfriend over their son, Cole, forced him to curtail his TV appearances and visibility beginning in the mid-1980s, when Brenner lived in Aspen, Colo.
"In a nutshell, I couldn't work more than 50 nights a year [out of town] or I'd be an absentee father," he said. "That was when they were giving out the talk shows, the sitcoms."
He was asked if he regretted his decision.
"I didn't even make a decision. I didn't even think about it. How could you not do it? I don't mean to sound noble," Brenner said. "Besides, I come from the slums of Philadelphia and everything in my life is profit. My downside is what most people would strive a lifetime to get to."
Brenner wrote five books, including the post-9/11 I Think There's a Terrorist in My Soup published in 2003. His last HBO special, David Brenner: Back with a Vengeance debuted live in 2000.
In a statement, his family said he left a last laugh: A final request that $100 in small bills be placed in his left sock "just in case tipping is recommended where I'm going."
Besides son Cole, Brenner is survived by his wife, Ruth, sons Wyatt and Slade and a grandson, Wesley, according to a statement from the family.
David Brenner wasn't married to Olympic skating champion Tai Babilonia, Abraham said, despite some reports that she is his surviving spouse. The pair had been engaged at one time, Abraham said.
Funeral plans were not immediately announced.