Macdonald was born Norman Gene Macdonald in Quebec City, Quebec. He began his career in stand-up comedy. Macdonald's first job was writing for The Dennis Miller Show (1992) and then Roseanne (1988). While writing for Roseanne (1988), he was noticed by Lorne Michaels, who liked Norm's stand up, and gave him his job on Saturday Night Live (1975).

Macdonald became widely popular when he became the Weekend Update anchor with his trademark line, "And now the fake news". He lasted from September 24, 1994 until December 13, 1997, when he was fired by Don Ohlmeyer, president of NBC on the west coast. His last weekend update was December 13, 1997 and he officially left the show in March 1998. His movie, Dirty Work (1998), which he began working on in the summer of 1997, came out 2 months later. In March 1999, his show, called Norm (1999), came out on ABC and had a 3-season run. During that time, he also starred in the movie Screwed (2000), opposite Dave Chappelle.