[4] Playing in his third season with Val-d'Or, he led the Foreurs to the 2007 QMJHL Finals with 31 points in the post-season, only to be swept by the Lewiston MAINEiacs in four games.

Letang excelled in his rookie season with Pittsburgh and was invited to the 2008 NHL YoungStars Game during All-Star weekend, alongside teammate Tyler Kennedy.

Entering the 2008–09 season, the Penguins' top two defencemen, Sergei Gonchar and Ryan Whitney, were both put on the long-term injured reserve, immediately increasing Letang's responsibilities on the team's blueline.

[8] During the season, Letang was also invited to his second NHL YoungStars Game during the 2009 All-Star weekend in his hometown of Montreal, playing for the Sophomores team.

With the departure of the Penguins' top defenceman, Sergei Gonchar, the following summer, Letang assumed a larger role with the club in 2010–11.

With a career-high 50 points (eight goals and 42 assists), Letang finished the season as the second-highest scorer for the Penguins, behind Sidney Crosby.

His efforts helped the Penguins to the fourth-best record in the NHL with 49 wins and 106 points despite long-term injuries to the team's top three centres – Crosby, Evgeni Malkin and Jordan Staal.

On January 23, 2012, Letang made the NHL 2012 All-Star roster as an injury replacement for Winnipeg's Dustin Byfuglien, joining teammates Evgeni Malkin and James Neal.

[12] On March 16, 2014, Dan Bylsma, then-head coach of the Penguins, announced Letang was cleared by doctors to return to full practice.

On April 19, 2016, in game three of the series, Letang was the subject of a controversial slash to the neck of Rangers' forward Viktor Stålberg.

He scored the Cup-winning goal in game six of the 2016 Stanley Cup Finals, against Martin Jones of the San Jose Sharks.

He finished fourth in voting for the James Norris Memorial Trophy as the NHL's top defenceman, and was named to the end of season second all-star team.

[22] With his prior eight-year deal concluding at the end of the 2021–22 season, Letang was poised to become an unrestricted free agent, but on July 7 he opted to sign a six-year, $36.6 million extension with the Penguins.

[25] Letang missed further time in January 2023, following the death of his father, Claude Fouquet, which caused him to leave prior to the 2023 NHL Winter Classic against the Boston Bruins.

In recognition of his performing despite multiple health and familial issues, Letang was named a finalist for the Masterton Trophy for the second time.

He won the first gold medal with Canada in Vancouver as the host country, then returned the next year in Sweden to score six points in six games as team captain.

Letang lost one of his closest friends, Luc Bourdon, who was a defensive prospect for the Vancouver Canucks, when he died in a motorcycle accident on May 29, 2008.