He played for the Boston Bruins, New York Islanders, Tampa Bay Lightning, Anaheim Ducks, Ottawa Senators, Los Angeles Kings, Montreal Canadiens, Philadelphia Flyers and Winnipeg Jets.

However, during the latter season, he joined Boston's American Hockey League (AHL) affiliate, the Providence Bruins on their run in the 2005 Calder Cup playoffs, making his professional debut.

Thompson signed an entry-level contract with the Bruins on July 20, 2005, and made his debut in the NHL with the team in 2006–07, playing four games; however, he spent the majority of the season with Providence in the AHL.

On June 29, 2014, Thompson was traded by Tampa Bay to the Anaheim Ducks in exchange for two picks in the 2015 NHL Entry Draft.

On December 14, the NHL department of player safety issued a three-game suspension against Thompson for his hit on Justin Faulk of the Carolina Hurricanes.

[15] On the first day of the 2017 free agency period, Thompson signed a two-year, $3.3 million contract with the Ottawa Senators, a deal that reunited him with his former Lightning coach Guy Boucher.

[16] Replacing Chris Kelly as the fourth-line center for Ottawa, it was the first time in eight NHL seasons that Thompson had played for a Canadian team.

[20] The Los Angeles Kings acquired Thompson and Dion Phaneuf from the Senators on February 13, 2018, in exchange for Marián Gáborík and Nick Shore.

[20] Thompson enjoyed the trade, which put him in the more physically aggressive Western Conference and allowed him to exercise his abilities as both a two-way player and as a penalty killer.

[25] The Kings as a whole struggled to score at the start of the season, and Thompson did not notch his first goal of the year until November 18 as part of a 5-3 loss to the Nashville Predators.

[29] Thompson and AHL call-up Dale Weise were part of a larger effort from general manager Marc Bergevin to rebuild Montreal's fourth line, which had not seen a goal since December 29.

[30] Flanked by Weise and Nicolas Deslauriers,[31] Thompson quickly became the Canadiens' everyday fourth-line center, playing in 25 of the 26 regular-season games following his trade while putting up one goal and six assists.

"[34] Responding to criticisms from sports journalists that he was slow on the ice, Thompson spent the offseason improving his diet and exercising in order to build lean muscle mass.

[35] Continuing to serve on the fourth line, Thompson also became an unofficial captain for the Canadiens during the 2019–20 season, mentoring rookie centers Nick Suzuki, Ryan Poehling, and Jesperi Kotkaniemi.

[36] "Uncle Nate", as many of the younger players referred to him, recorded four goals and 10 assists in 63 games with Montreal, going −2 and winning 55.1 percent of his face-offs.

[38] Coach Alain Vigneault was in need of more veteran skaters, and inserted Thompson into Connor Bunnaman's spot on the fourth line.

On March 11, Thompson was diagnosed with a left knee sprain resulting from a collision with Ondrej Kase of the Bruins, and he was expected to miss at least two weeks.

He agreed to return to the Los Angeles Kings organization in accepting a professional tryout to participate in training camp and the pre-season.

[63] Thompson married his first wife, former Boston College Eagles women's ice hockey player Cristin Stuart, in July 2013.

He began drinking alcohol around the age of 11, and by his mid-20s, he was taking a number of recreational drugs, including cocaine, MDMA, and psilocybin mushrooms.