After playing a full season with the Lumberjacks, openings in the Wild's roster due to injuries led to Dupuis making his NHL debut on April 2, 2001.

[19] Following the signing, Dupuis along with four other players were assigned to the Wild's top minor affiliate in the International Hockey League, the Cleveland Lumberjacks.

[20] It took more than a month from the start of the 2000–01 IHL season for Dupuis to begin producing, scoring his first professional goal on November 12 in a 3–0 victory over the Kansas City Blades.

[1] Dupuis entered the 2001–02 season in competition with Matt Johnson, Sylvain Blouin, and Cam Stewart for a left wing job on the Wild.

[1] For the 2002–03 season, Dupuis continued to participate in the Wild training camp but did not have to push as hard as the prior year for a roster spot.

[33] The success was cited by Wild head coach Lemaire from a line that had Dupuis with rookie Pierre-Marc Bouchard and Marián Gáborík.

[35] With Dupuis's help, the Wild made their first postseason appearance in franchise history as the sixth seed, matched up against the third-seeded Colorado Avalanche.

[36] The Wild won their first series 4–3 and advanced to the Western Conference Semifinals against the Vancouver Canucks, where Dupuis suffered a lower-body injury.

Dupuis returned quicker than expected from injury and scored two goals in game seven to secure a 4–2 victory and an advance to the Conference Finals against the Anaheim Mighty Ducks.

[1] On July 1, 2003, the Wild extended a qualifying offer to Dupuis, who was classified as a restricted free agent following the expiration of his three-year entry-level contract.

[1] With the 2004–05 NHL lock-out putting a halt on the 2004–05 season, Dupuis joined a four-on-four charity hockey series named the McDonald's Caravan.

The series included 40 NHL players such as Roberto Luongo, Mike Ribeiro, and Vincent Damphousse as they toured around Quebec from late October to mid-December.

[50] Dupuis returned on February 8 against the Los Angeles Kings, where he and Marián Gáborík together scored 5 powerplay goals in a 5–1 win, a franchise record.

[56] Tom Renney, the Rangers head coach said that Dupuis was a good fit for the team as a "real sound defensive player", along with his speed and offensive ability being an extra help.

[55] Wild general manager Doug Risebrough on February 26 told reporters he made the trade to improve locker room chemistry.

[58] On February 27, 2007, he was traded along with the Rangers' third-round pick in the 2007 NHL entry draft to the Atlanta Thrashers for prospect Alex Bourret.

[61] After Jon Sim was declared out for a week due to a broken left orbital bone, Dupuis filled in on the first line with Ilya Kovalchuk and Keith Tkachuk.

[66] Dupuis expected to factor in on the penalty kill again, which had ranked 26th the previous season, alongside offseson additions Éric Perrin and Todd White.

[69] On February 9, 2008, Dupuis was traded to the Pittsburgh Penguins, along with Marián Hossa, in exchange for Colby Armstrong, Erik Christensen, Angelo Esposito and their first-round pick in the 2008 NHL Entry Draft.

[82] As the season continued, Dupuis remained on Crosby's wing until head coach Michel Therrien was replaced with Dan Bylsma in February 2009.

[83] Following the Penguins Stanley Cup win, Dupuis was informed by Bylsma that his role with the team depended upon him returning to training camp in better shape.

[95] The trio immediately found success as a line and helped lead the Penguins to a 13–1–1 record through November, including 10 consecutive wins.

[98] After Crosby suffered a concussion during the 2011 NHL Winter Classic, the team tested Mark Letestu as the new centre between Kunitz and Dupuis.

[102] While Crosby remained out for the majority of the 2011–12 season due to lingering health issues, Dupuis established career-highs in goals with 25, assists with 34, and points with 59 through 82 games.

[107] The second line combined for 15 goals during the Penguins 11-game winning streak that eventually helped them clinch a spot in the 2012 Stanley Cup playoffs.

[119] As an impending free agent on July 2, 2013, Dupuis opted to remain in Pittsburgh and signed a four-year, $15 million contract extension.

[120] On October 16, during the second period of a game against the Dallas Stars, Dupuis was crosschecked to the ice by an opponent and while prone was struck by the puck near the back of his neck on a shot by teammate Kris Letang.

[123] Dupuis returned to play in the 2015–16 season, but suffered a lower back injury in October and was expected to miss four to five weeks to recover.

[128] On February 17, 2016, Dupuis received the inaugural Dapper Dan Courage Award as a "Pittsburgh-area athlete who best exemplifies the meaning of perseverance by overcoming adversity while serving as an inspiration to their teammates or organization.

[133] He joined the Penguins organization while still on long-term injury reserve for the 2016–17 season to work as a part-time scout out of Quebec, along with doing player development for the franchise.