Lupul suffered a fractured forearm after a shot from teammate Dion Phaneuf hit him. Lupul, who signed a five-year contract extension on Sunday, did not return.
Nikolai Kulemin added three assists as Toronto spoiled Pittsburgh's home opener by giving the Penguins a reality check.
Sidney Crosby and reigning NHL MVP Evgeni Malkin scored their first goals of the season for Pittsburgh, but the Penguins struggled with Toronto's speed and failed to play with the kind of discipline that highlighted opening weekend wins over Philadelphia and the New York Rangers.
Marc-Andre Fleury stopped 19 shots for the Penguins but Pittsburgh couldn't get off to its first 3-0 start in 18 years.
The Penguins began the shortened 48-game season with rousing road victories over the Flyers and Rangers, the kind of electric start that did little to dampen expectations about Pittsburgh being an early Stanley Cup favourite.
And that was without Crosby or Malkin finding the back of the net.
Malkin ended his drought _ such as it is for a player who scored 23 goals while playing in Russia as the lockout dragged on _ late in the first period when he stuffed a pass from Crosby in between Reimer's legs to give Pittsburgh a 1-0 lead.
For the first time this season, it didn't hold up.
Pittsburgh coach Dan Bylsma spoke openly about the problems Toronto's quickness provides, saying his team gave the Maple Leafs a little too much room to operate last season.
Any attempts by the Penguins to tighten up, however, came up woefully short. Even with Bylsma experimenting with his lines _ on a couple of occasions he paired Crosby and Malkin in even-strength situations _ Pittsburgh looked a step slow.
Toronto scored twice early in the second period to jump in front, including van Riemsdyk's first goal for Toronto after being acquired in an off-season trade with the Flyers. Crosby needed just 25 seconds to tie it, beating Reimer between the legs on a breakaway for his first goal in 280 days.
The speedy Maple Leafs just kept coming, with van Riemsdyk collecting his second goal of the night _ and his 101st career point _ after intercepting a sloppy clearing attempt by Malkin and firing the puck over Fleury's glove to give Toronto a 3-2 lead.
A Pittsburgh turnover left Grabovski all alone on the doorstep slipping the puck past Fleury to give Toronto a 4-2 lead and sending the largest crowd in the brief history of Consol Energy Center heading for the exits a little early.
NOTES: The Maple Leafs scratched defencemen Cody Franson and Mark Fraser and centre David Steckel. Defencemen Ben Lovejoy, Robert Bortuzzo and centre Dustin Jeffrey ... Toronto hosts the New York Islanders on Thursday night. The Penguins travel to Winnipeg on Friday ... Pittsburgh offered free food and half off merchandise to all fans as an apology following the 119-day lockout.