According to Deadline, the comedian had been privately battling cancer for nine years.
Macdonald's longtime producing partner and friend Lori Jo Hoekstra was reportedly at his side when he passed.
"He was most proud of his comedy," Hoekstra told Deadline. "He never wanted the diagnosis to affect the way the audience or any of his loved ones saw him. Norm was a pure comic. He once wrote that ‘a joke should catch someone by surprise, it should never pander.’ He certainly never pandered. Norm will be missed terribly."
Macdonald was the son of two schoolteachers raised in Quebec City, Canada, and worked as a standup comic before starting out as a writer on "Roseanne" in 1992.
Then, he became an "SNL" cast member from 1993 until 1999. He famously anchored the show's Weekend Update sketch for three seasons and was replaced by Colin Quinn.
Macdonald became known for his esoteric impressions, including Burt Reynolds, who gave Will Ferrell’s Alex Trebek character grief on "Celebrity Jeopardy." He also impersonated Bob Dole, Larry King and David Letterman.
After leaving "SNL," Macdonald had his own comedy show, "The Norm Show," from 1999-2001 on ABC playing a former NHL player kicked out of the league for gambling and tax evasion and forced into community service as a social worker.
Later, he had his own talk show on Netflix for one season in 2018.
Macdonald was married to Connie Vaillancourt from 1988 to 1999 and the couple had a son, Dylan, born in 1993.
The Associated Press and Fox News' Julius Young contributed to this report.