The Senators scored all four goals in the third period to win the second of two split-squad games against the Maple Leafs. Toronto won the first game 4-1.
Matthews won the Hart Trophy voted as the NHL most valuable player last season, when he led the League with 60 goals.
Calle Jarnkrok scored twice in his Toronto debut after signing a four-year, $8.4 million contract ($2.1 million average annual value) on July 15. He gave the Maple Leafs a 1-0 lead at 1:07 of the second period and made it 2-0 at 11:01.
Angus Crookshank, Josh Norris, Mark Kastelic and Tyler Motte scored for the Senators.
Crookshank cut it to 2-1 at 4:49, and Norris scored a power-play goal at 13:42 to tie it 2-2. Norris signed an eight-year, $63.6 million contract ($7.95 AAV) on July 14.
Kastelic gave Ottawa a 3-2 lead at 13:42, and Motte scored into an empty net at 19:40 for the 4-2 final.
Ilya Samsonov did not allow a goal on 16 shots in 39:40 in his Maple Leafs debut. He signed a one-year, $1.8 million contract July 13. Keith Petruzzelli made seven saves in relief.
Anton Forsberg allowed one goal on 14 shots in 30:38, and Mads Sogaard made eight saves in relief for the Senators.
Maple Leafs 4, Senators 1: Mark Giordano had three assists for the Toronto Maple Leafs in a 4-1 win against the Ottawa Senators in the first of two split-squad games at Scotiabank Arena on Saturday.
Alex Steeves scored twice, and Justin Holl had a goal and an assist for the Maple Leafs. Erik Kallgren made seven saves on eight shots before being replaced by Dylan Ferguson (nine saves) in the third period.
Tim Stutzle scored, and Alex DeBrincat, who was acquired in a trade with the Chicago Blackhawks on July 7, had an assist for the Senators. Cam Talbot made 10 saves on 13 shots in his Ottawa debut. He was acquired in a trade with the Minnesota Wild on July 12. Kevin Mandolese stopped all 11 shots he faced after replacing Talbot in the second period.
Claude Giroux, who signed a three-year contract in free agency on July 13, did not have a point in his Senators debut.
It was the preseason opener for both teams.
Stutzle gave Ottawa a 1-0 lead at 11:15 of the first period before Toronto scored four straight goals.
The Maple Leafs scored three times in 2:14 in the second period. Holl tied the game 1-1 at 5:59 before Denis Malgin made it 2-1 at 7:55 and Steeves extended the lead to 3-1 at 8:13.
Steeves scored his second of the game, an empty-net goal with 1:19 remaining, for the 4-1 final.