Mikael Samuelsson also had two goals, and Pavel Datsyuk added a goal and two assists for Detroit, which won its fifth in six games. Mathieu Schneider added three assists, and Tomas Holmstrom had two. Dominik Hasek stopped 21 shots.
Bryan McCabe scored for Toronto, which lost its seventh in a row. Andrew Raycroft made 18 saves off 22 shots before giving way to J.S. Aubin, who stopped eight of nine shots.
The Red Wings led 2-0 after the first period.
Samuelsson put a cross-crease pass into the open side of the net at 9:53 and Zetterberg tapped in a loose puck with 2:44 left in the period.
Samuelsson's second goal made it 3-0 with 9:18 remaining in the second period. He beat Raycroft with a wrist shot from the high slot.
McCabe got Toronto on the board with a power-play goal with 7:56 remaining in the middle period, beating Hasek with a one-timed shot from the slot.
But Zetterberg's second goal, with only 1.6 seconds left in the period, restored Detroit's three-goal lead. He got his 11th goal by putting in a loose puck off of a goal-mouth scramble.
Datsyuk's goal came 1:15 into the third period.
Notes: The teams hadn't played since Dec. 6, 2004. Toronto's last game in Detroit was Feb, 27, 2003. ... Detroit was without D Niklas Kronwall (groin) and LW Johan Franzen (knee). ... Maple Leafs coach Paul Maurice coached the Ontario Hockey League Major Junior franchise then known as the Detroit Jr. Red Wings to the Memorial Cup Tournament in 1995. ... About 2,000 Toronto fans attended the game. ... Datsyuk's goal was his third in three games. ... Hasek earned his ninth straight win over Toronto.