The Red Wings earned two huge points in their quest to qualify for the Stanley Cup playoffs for a 23rd consecutive season.
Daniel Alfredsson also scored for the Red Wings (31-24-13), who are one point behind the Columbus Blue Jackets for the second wild-card spot in the Eastern Conference. The Blue Jackets lost 3-1 to the Carolina Hurricanes.
Detroit will host the Pittsburgh Penguins on Thursday.
"It's a division rival ... big game for us, big win for us," Alfredsson said. "We'll enjoy this for a few hours and then back to work tomorrow."
Jake Gardiner and James van Riemsdyk scored for Toronto (36-26-8), which has dropped back-to-back games. James Reimer made 28 saves for the Maple Leafs, who own the first wild-card position race. Toronto, which went 2-3-0 on a five-game road trip, gets right back at it Wednesday when it will host the Tampa Bay Lightning.
"We have to come to play tomorrow and get the two points," Gardiner said.
Nyquist broke a scoreless tie 12:50 into the first period. With the teams at even strength, he poked the puck past Maple Leafs defenseman Tim Gleason in the neutral zone, then raced past Cody Franson before beating Reimer with a backhand shot for his 18th goal of the season.
The Red Wings doubled their lead on Nyquist's second of the game 2:06 into the third period. Nyquist intercepted Joffrey Lupul's pass in the Red Wings' zone and blew past the Maple Leafs' defense before firing a wrist shot from the right circle past Reimer to make it 2-0.
"It's nice to get up with a couple of goals," Nyquist told Fox Sports Detroit. "Lately, that hasn't happened too often. It helped our team defense to get up a couple goals. It's tough when you're always chasing from behind or when you're even, so it's nice to get up a couple."
Toronto cut the deficit in half when Gardiner scored on the power play at 8:24. With Detroit defenseman Kyle Quincey off for high sticking, Maple Leafs defenseman Morgan Rielly sent a long pass from his own blue line that went off the boards behind the Detroit net and bounced out to Gardiner, who was in alone on Howard and beat the Red Wings goalie via the forehand for his ninth goal of the season.
Nazem Kadri thought he had tied the game for the Maple Leafs at 10:32, but relays concluded Kadri used a distinct kicking motion with his right skate to poke a loose puck in the crease past Howard. Had it counted, it could have been a goal that changed the complexion of the road trip.
"It was average," Kadri said of the trip. "There was some good and bad throughout the five games."
Alfredsson ended a nine-game drought and restored Detroit's two-goal lead with 2:33 remaining in regulation. He came down on a 2-on-1 with David Legwand, took the latter's feed and wristed a shot from the slot past Reimer to make it 3-1. It was Alfredsson's 15th goal of the season and first since Feb. 8.
Van Riemsdyk got Toronto within one at 18:47 when he snapped a seven-game drought by scoring 27th goal of the season, but Toronto managed one shot against Howard in the final 73 seconds.
Detroit defenseman Jonathan Ericsson sustained a broken finger on his left hand and did not play in the third period. The Red Wings are already without injured forwards Pavel Datsyuk, Henrik Zetterberg, Stephen Weiss, Justin Abdelkader and Darren Helm, along with goaltender Jonas Gustavsson. Detroit entered Tuesday with 313 man-games lost due to injury.
"We get someone hurt every day and they never come back, so I guess he's out for a bit. I don't really know," coach Mike Babcock said. "There's a hand specialist looking at him. He's got a broken finger. In the old days you just tape it back together and you want him to keep playing, but I don't know what the rules are."
Added Howard: "You kind of just shake your head. Hopefully we don't lose another guy, because now it's just getting to be mind-boggling."
Red Wings forward Landon Ferraro made his NHL debut and had one shot on goal in 9:45. A second-round pick (No. 32) at the 2009 NHL Draft, Ferraro is the son of former NHL center Ray Ferraro.