In the 2001–02 season, his rookie year, Cole scored six goals during the 2002 Stanley Cup playoffs. Additionally, he was one-third of the "BBC Line," which also featured Bates Battaglia and Rod Brind'Amour, during the Hurricanes' Stanley Cup run in 2002. On December 19, 2005, Cole was chosen to represent Team USA ice hockey for the 2006 Winter Olympics in Turin. He was named alongside fellow Clarkson University alumnus Craig Conroy, then of the Calgary Flames. He also represented Team USA the next year at the 2007 IIHF World Championship in Moscow. On March 4, 2006, Cole suffered a fractured vertebra in his neck after getting hit by Pittsburgh Penguins defenseman Brooks Orpik. The injury kept him out of the lineup until Game 6 of the 2006 Stanley Cup Finals, where the Hurricanes won the Stanley Cup in Game 7 over the Edmonton Oilers. On November 12, 2007, Cole went head-first into Florida Panthers goaltender Tomáš Vokoun; he was face down on the ice for over five minutes and was escorted off the ice via stretcher. It was a neck injury but not serious, and he traveled with the team to Tampa Bay. Cole was the first player in the NHL to ever be awarded two penalty shots in the same game. On July 1, 2008, Cole was acquired by the Edmonton Oilers in exchange for Joni Pitkänen. On January 14, 2009, Cole, as a member of the Oilers, recorded his fifth NHL hat-trick against the Washington Capitals on goaltender José Théodore. Cole set an unofficial NHL record in the Fastest Skater event by skating around the entire ice at Rexall Place with a time of 13.117 seconds. On March 4, 2009, Cole was traded back to Carolina in exchange for Patrick O'Sullivan and a second-round draft pick; O'Sullivan was traded to Carolina for Justin Williams and second-round pick earlier that day. On July 1, 2009, the Hurricanes signed Cole to a two-year, $5.8 million contract, which paid $2.8 million in 2009–10 and $3 million in 2010–11). On December 5, 2009, Cole scored his sixth career hat-trick against the Vancouver Canucks in Raleigh. The second goal went off the skate of former Clarkson University teammate, and then-Canuck, Willie Mitchell. Cole scored the third goal on an empty-net after goaltender Andrew Raycroft was pulled in favor for an extra attacker in the last minute of play. On July 1, 2011, Cole signed a four-year, $18 million contract as a free agent with the Montreal Canadiens. Cole wore jersey number 72 for the Canadiens. During his first season with the Canadiens in 2011–12, Cole set career highs with 35 goals and 61 points. On March 23, 2012, Cole scored a natural hat-trick just 5:41 into a game against the Ottawa Senators, setting a Canadiens record for the quickest hat-trick from the start of a game. On February 26, 2013, during the lockout-shortened 2012–13 season, after a slow start offensively, Cole was traded to the Dallas Stars in exchange for Michael Ryder and a third-round draft pick in 2013. In 28 games with Dallas, Cole would record six goals and one assist as the Stars would miss the 2013 playoffs. On March 1, 2015, the Stars traded Cole to the Detroit Red Wings in exchange for Mattias Bäckman, Mattias Janmark-Nylén and a second-round draft pick in 2015. On April 8, it was announced that Cole would miss the remainder of the season with a spinal contusion he suffered on March 24 in a game against the Arizona Coyotes. On September 20, 2017, Cole signed a one-day contract with the Carolina Hurricanes and subsequently announced his retirement from the NHL
