The Rangers played their home opener after starting the season with seven road games, two of them in Europe. New York went 3-2-2 before playing a game in Madison Square Garden.
Toronto won for the sixth time in nine games to start the season.
It was a 1-1 contest heading into the third period, but Lupul scored his fifth goal of the season on a wrist shot 2:11 into the period. Clarke MacArthur and Mike Brown both registered their first goal of the season to give the Maple Leafs a 4-1 advantage.
Center Tim Connolly, who played the previous eight seasons with Buffalo, made his Toronto debut after suffering an injury in training camp. He did not get off a shot and spent 2 minutes in the penalty box.
Jonas Gustavsson picked up the victory by making 28 saves. The loss went to Henrik Lundqvist, who stopped 32-of-36 shots.