Joining "Saturday Night Live", Macdonald distinguished himself as the sardonic host and writer of the "Weekend Update" segment, although by 1998 he was relieved of his duties when NBC executive Don Ohlmeyer reportedly intervened and had Macdonald removed. (The press speculated that Macdonald's frequent jibes against Ohlmeyer crony O J Simpson as well as the feeling that he was a "loose cannon", partly for his use of the F-word in an April 1997 live broadcast, were factors in his dismissal.) Over the course of five seasons on "SNL", he also excelled at impersonating such figures as comedian George Burns, Dr Jack Kevorkian and TV newscasters Charles Kuralt and Andy Rooney. A memorable moment came in April 1996 when Macdonald impersonated presidential candidate Steve Forbes opposite the real Steve Forbes.
Macdonald made his film debut alongside fellow "SNL"-er Adam Sandler in "Billy Madison" (1995) and was seen playing a network reporter in "The People vs. Larry Flynt" (1996). He co-scripted and co-starred in "Dirty Work" (1998), a big screen comedy, as well as provided the voice of Dog in the remake of "Dr. Dolittle" (also 1998), starring Eddie Murphy.