In his professional career, Lupul played in the NHL for the Anaheim Ducks, Edmonton Oilers, Philadelphia Flyers and Toronto Maple Leafs.

The following season, Lupul made the final roster for Canada and played in the 2003 World Junior Ice Hockey Championships in Halifax, Nova Scotia.

[1] After the 2005–06 season, Lupul was traded to the Western Conference champion Edmonton Oilers (along with Ladislav Šmíd and draft picks) in exchange for Chris Pronger on July 4, 2006.

[2] On July 1, 2007, after just one season with Edmonton in which he scored 16 goals, Lupul was traded (alongside Oilers captain Jason Smith) to the Philadelphia Flyers in exchange for Joni Pitkänen, Geoff Sanderson and a third-round draft pick in 2007.

[3] During the 2007–08 season, his first with the Flyers, Lupul was diagnosed with a spinal cord contusion after a collision with teammate Derian Hatcher in a game against the Toronto Maple Leafs on January 5, 2008.

After helping the Flyers reach the Eastern Conference Finals, in which Philadelphia fell to rivals Pittsburgh, Lupul agreed to a four-year contract extension with the team on July 21.

Nonetheless, he finished with a career-high of 67 points on the year despite playing in just 66 games, marking the first time in his NHL career he scored at least a point-per-game pace.

[10] At the end of the season, Lupul was a finalist for the Bill Masterton Memorial Trophy—awarded annually to the NHL player best exemplifying qualities in perseverance, sportsmanship and dedication to hockey—which was ultimately awarded to Max Pacioretty of the Montreal Canadiens.

While chasing the puck deep in his own zone, Lupul was hit by two Flyers simultaneously, one of which accidentally contacted his head, resulting in a concussion.

[17] Facing a decline in offensive production and a growing reputation as an injury-prone player (having missed 40% of the Maple Leafs' games over the past four seasons due to injury),[17] Rumours began to circulate as early as February 2016 that there was concern if Lupul could continue to play at the NHL level anymore.

[21] These accusations prompted the NHL to administer a second physical by an independent doctor, which he subsequently failed and confirmed the Maple Leafs' initial claim he was unfit to play.

He posted two goals and one assist for a total of three points in six games as Canada finished with the silver medal, falling 3–2 to Russia in the tournament final.