Letang signed a six-year, $36.6 million contract with the Pittsburgh Penguins on July 7, 2022, then-general manager Ron Hextall saying he "epitomizes what it means to be a Pittsburgh Penguin" after he set an NHL career-high of 68 points (10 goals, 58 assists) in 78 games of his age 35 season. He entered his 17th NHL season third among defensemen in points (650) since joining the NHL in 2006-07, a two-time NHL Second Team All-Star (2013, 2016), and three-time Stanley Cup winner (2009, 2016, 2017).

On April 2, 2023, Letang became the third Penguins skater to play 1,000 games, joining Sidney Crosby and Evgeni Malkin, when Pittsburgh defeated the Philadelphia Flyers 4-2 at PPG Paints Arena. He was awarded the Bill Masterton Memorial Trophy, presented annually 'to the player who best exemplifies the qualities of perseverance, sportsmanship and dedication to hockey," after recovering from a stroke, the second of his lifetime, and mourning the death of his father within a span of four weeks during the season. He remained a Penguins cornerstone in his 17th season, ranking 10th among NHL players in ice time per game (24:51) and getting 41 points (12 goals, 29 assists) in 64 games.

Letang had an assist in a 4-2 loss to the Carolina Hurricanes on Nov. 18, 2023, becoming the 10th defenseman in NHL history to reach 700 points (157 goals, 543 assists in 1,021 games played) with a single franchise. He then became the first defenseman in NHL history to get five points in one period with five assists during a six-goal second in the Penguins' 7-0 victory at the New York Islanders on Dec. 27, 2023. His six assists made him the first in the NHL at his position with that many in one game since Gary Suter on April 4, 1986.

He had an assist in his 1,100th NHL game, a 3-1 win against the Montreal Canadiens at PPG Paints Arena on Nov. 2, 2024. He had two assists in a 5-1 win against the Vancouver Canucks on Oct. 21, 2025, to become the 20th defenseman in NHL history with 600.

Letang was selected by the Penguins in the third round (No. 62) of the 2005 NHL Draft out of Val-d'Or in the Quebec Major Junior Hockey League. In 2007, he won three awards in the QMJHL: the Emile Bouchard Trophy as the top defenseman, the Kevin Lowe Trophy as the best defensive defenseman and the Paul Dumont Trophy as the best personality.

Representing Canada, Letang won a gold medal at the 2006 and 2007 IIHF World Junior Championship after winning a silver medal at the 2005 IIHF World Under-18 Championship.

Letang made his NHL debut Oct. 5, 2006, against the Philadelphia Flyers, and scored his first NHL goal seven days later, against the New York Rangers.

As a rookie in 2007-08, he had six goals and 17 points in 63 games and averaged 17:07 of ice time in 16 Stanley Cup Playoff games to help the Penguins reach the Cup Final.

In his second full season, Letang averaged 21:09 per game and scored 33 points (10 goals, 23 assists) in 74 games. He scored 13 points (four goals, nine assists) in 23 playoff games to help the Penguins win the Stanley Cup for the first time since 1992.

Injuries limited Letang to 86 games from 2011-13, and in 2013-14 he missed 10 weeks after having a minor stroke Jan. 29 that limited him to 37 games.

Letang had 67 points (16 goals, 51 assists) in 71 games in 2015-16, averaged a team-high 26:57 of ice time per game and was named to the NHL Second All-Star Team for the second time. His ice time increased to 28:53 in the playoffs, when he scored 15 points (three goals, 12 assists) in 23 games to help Pittsburgh win another Stanley Cup championship.

Letang's 2016-17 season ended Feb. 21, the result of a herniated disc in his neck. He had 34 points (five goals, 29 assists) in 41 games but sat out the playoffs when the Penguins won the Cup for the second consecutive season. He rebounded with 51 and 56 points, respectively, in the next two seasons, and on Oct. 13, 2019 he became the first defenseman in Penguins history to score 500 points.