[20] Matthews was approached by Lions head coach Marc Crawford, who was awed by his skating and puck possession while scouting the 2015 World U18 Championships.

[22] Matthews' stint in the NLA ended earlier than expected when the top-seeded Lions were swept in the first round of the 2016 playoffs by SC Bern.

Matthews had been widely expected to go first overall for several months leading up to the event, consistently topping prospect charts and major scouting reports.

[26] On July 21, the two parties finalized a deal, with Matthews signing a three-year, entry-level contract that included the maximum allocation of performance bonuses.

[32] Two months later, in the NHL Centennial Classic against the Detroit Red Wings, Matthews scored the game-winning goal in overtime, securing a 5–4 victory for the Maple Leafs.

[41] In recognition for his accomplishments throughout the year, Matthews was awarded the Calder Memorial Trophy as the NHL's top rookie, with 164 of 167 first-place votes.

[53] On October 27, after being hit by Winnipeg Jets defenseman Jacob Trouba in a 3–2 Maple Leafs win, Matthews sustained a left shoulder injury and was set to be sidelined for at least four weeks.

[54] After missing 14 games, Matthews returned to the lineup on November 28 against the San Jose Sharks; he recorded two goals and one assist in Toronto's 5–3 win.

[3] However, the Maple Leafs were eliminated by the third seeded Boston Bruins in seven games for the second straight season, surrendering a 3–2 series lead in the process this time around.

[63] He was then named to his fourth straight All-Star appearance, but due to an "ongoing wrist condition", he would not participate in the festivities; he was replaced by Senators winger Brady Tkachuk.

[64] Matthews would finish the abbreviated regular season with career-highs in goals (47) (a 55-goal pace in a full 82 game campaign) and 43 assists for 80 points.

Matthews scored twice in the five-game series, including the overtime winner to cap off an improbable three-goal rally in the last five minutes of Game 4.

However, after this, he began scoring at a prodigious pace, eventually overtaking Edmonton Oilers center Leon Draisaitl to lead the NHL in goal-scoring by the midpoint of the season.

[75] On March 14, 2022, Matthews was suspended for two games after crosschecking Buffalo Sabres defenseman Rasmus Dahlin at the 2022 Heritage Classic the day before.

[77] Days later, Matthews scored his seventh career hat-trick in an April 4 game against the Tampa Bay Lightning and tied the franchise record for goals in a season (54), set by Rick Vaive in 1981–82.

This also marked the highest goal total for an NHL player in a single season since Tampa Bay Lightning center and captain Steven Stamkos' 60-goal 2011–12 campaign.

[82] This secured his second straight Rocket Richard Trophy and second in his career altogether, joining Ovechkin and Pavel Bure as the only players to win it consecutively.

[83] Matthews was later named a finalist for the Hart Memorial Trophy and Ted Lindsay Award, both for the second consecutive year; Edmonton Oilers center and captain Connor McDavid was a finalist alongside Matthews for both awards, as were New York Rangers goaltender Igor Shesterkin and Nashville Predators defenseman and captain Roman Josi for the Hart and Ted Lindsay, respectively.

[86] Advancing into the 2022 playoffs, Matthews and the Maple Leafs drew the two time defending Stanley Cup champion and fifth seeded Tampa Bay Lightning in the first round.

[86] Despite scoring at a slower pace in the first half of the season, on January 3, 2023, Matthews became the fastest Leafs player to register 500 career points in a game against the St. Louis Blues.

[96] The Maple Leafs finished second in the Atlantic Division, third in the Eastern Conference and fourth in the league, setting up a second consecutive first-round meeting with the Tampa Bay Lightning.

The Leafs were commonly seen as the frontrunners at the beginning of the series being the higher seeded team; however, the historical record of past failures in advancing beyond the first round since 2004 was widely recognized.

[97][98][99] Many suggested that the outcome of the series would have major ramifications for the team going forward, including the status of both general manager Kyle Dubas and head coach Sheldon Keefe, and also for the prospect of Matthews re-signing in Toronto, which he would become eligible to do in the summer.

[103] That October, Matthews began the 2023–24 season by scoring his eighth career hat trick, as the Maple Leafs defeated the Canadiens 6–5 in a shootout.

[110] Matthews helped lead the United States men's national under-18 ice hockey team to gold at the 2014 IIHF World U18 Championship.

He did so again in the 2015 Championship, leading the tournament in scoring and being named the Most Valuable Player (MVP), as well as earning the top forward slot on the Media All-Star Team.

Later that year, Matthews played with the United States national men's senior team at the 2016 IIHF World Championship, during which he led the Americans in point scoring.

Following the Toronto Maple Leafs' first-round elimination in the 2017 playoffs, he was advised by the team to forego participating in the 2017 IIHF World Championship and to rest instead.

[124] He is a fan of players Jonathan Toews and Anže Kopitar due to their all around offensive and defensive game, and has had his playing style compared to them.

On June 19, 2020, the Toronto Sun reported that Matthews had tested positive for COVID-19 while at home in Scottsdale, Arizona before the start of training camp.