Frederik Andersen made 34 saves for the Maple Leafs (26-17-7), who won for the first time in three games (1-1-1).
It was the first game for each team since Jan. 18.
WATCH: [All Maple Leafs vs. Predators highlights]
"It was a good response," said Toronto forward Jason Spezza, who scored his second goal in the past seven games. "Coming out of a break can be difficult games. I thought it was a good match for our team, just coming out and getting a lead. I thought we controlled play for a lot of time. I think there's still things that we can do better, but for the most part we did a lot of good things, and that's why we got rewarded with a win."
The Predators (22-19-7) have lost three of their past four games.
"In the second period, we just got away from it," Nashville coach John Hynes said. "We just got away from the identity that we want to play with. The hardness that we need to play with to be able to win, managing the puck, consistency in the performances throughout the lineup, that was where the game got away from us."
William Nylander gave the Maple Leafs a 1-0 lead at 4:13 of the first period when he scored on a breakaway off a stretch pass from Sandin. Nylander's 23rd goal of the season established a new NHL career high and extended his goal streak to four games.