Sam Lafferty and Philipp Kurashev scored, and Petr Mrazek made 37 saves for the Blackhawks (16-32-5), who have lost five of six (1-4-1), including 4-0 at Montreal on Tuesday.
"I thought they obviously came out guns a-blazing," Chicago coach Luke Richardson said. "An unfortunate bounce for [Jake] McCabe, catching an edge and he went down on the first goal, but I thought we reacted well, but then another bounce [off Connor Murphy's stick]. I thought our guys pushed back after two tough bounces, but they really came out skating in the first half of the game.
"Our guys fought to the end, they were pushing, there was no give-up, guys were doing all the right things. It's just that's a big team, and when you get behind early and you're chasing it the whole game, that's what we tried to avoid."
Sandin put Toronto up 2-1 at 8:14 of the first period when his shot from the left hash marks along the side boards deflected off Murphy's stick.
The Maple Leafs thought they added to the lead at 8:29, but video review determined Alex Kerfoot preceded the puck into the offensive zone prior to his goal.
Matthews made it 3-1 at 11:21 when he shot from just outside the left hash marks in the slot after taking a pass from Nylander, who got the puck by the left hash marks along the side boards and skated towards the blue line before sending pass from the top of the right face-off circle back across the ice.
"I think he's just all over it and just the consistency factor has been really great to see," Matthews said of Nylander. "He's just all over it every single game, he's moving his feet and it's just been a lot of fun to watch. It's a treat to play with him."