Matthews scored Toronto's sixth goal of the game into an empty net with 2:06 left in regulation. He moved past Leon Draisaitl (49 goals) of idle Edmonton for the league goal lead and became the first Maple Leafs player to reach the milestone since Dave Andreychuk scored 53 in 1993-94.
"I don't know if I ever really envisioned it being an empty-netter goal, but I'll take it," Matthews said. "I had some good chances tonight, just didn't go in.
"Fortunately that last one did."
Matthews joined Andreychuk, Rick Vaive (three times) and Gary Leeman as the only Maple Leafs players to reach the half-century goal mark.
"Really special to be able to do it here in front of all the fans," said Matthews, whose team hits the road for four straight starting Saturday in Philadelphia. "The energy, the atmosphere and all that goes into it just makes it much more fun."
Matthews was twice robbed of 50 goals by COVID-19. He found the back of the net 47 times in 70 games in 2019-20 before the pandemic abruptly ended the regular season before putting up 41 in 52 contests over the course the 2020-21 coronavirus-shortened campaign to win his first Maurice (Rocket) Richard Trophy as the NHL's top goal scorer.
Thursday was Matthews' 62nd game of the season -- he missed three because of injury and two via suspension -- while Draisaitl has suited up for each of Edmonton's 68 contests.
According to ESPN Stats & Information research, Matthews is the fastest player to reach 50 goals in a season since 1995-96, when four players accomplished the feat -- Mario Lemieux (50 games), Jaromir Jagr (59 games), Alexander Mogilny (60 games) and Peter Bondra (62 games)
The Associated Press contributed to this report.