Karlsson is a three-time winner of the James Norris Memorial Trophy as the NHL's best defenceman, winning the award in 2012, 2015, and 2023.

Karlsson made his Elitserien debut for Frölunda HC on 1 March 2008, recording 8:48 of ice time during a sold out home game in Scandinavium against league leaders HV71.

Karlsson scored the game-winning goal, assisted by Tomi Kallio and Magnus Kahnberg, with a slap shot in overtime during a man advantage.

The selection was made by Ottawa's captain Daniel Alfredsson, a native of Gothenburg, who played for Frölunda before entering the NHL.

A few weeks before the 2008–09 Elitserien season premiere, Frölunda announced that Karlsson was brought up to the senior team as a regular roster player.

[citation needed] After struggling in nine regular season games with Ottawa, he was assigned to the team's American Hockey League (AHL) affiliate, the Binghamton Senators.

[9] The following day, Karlsson was announced as the winner of the James Norris Trophy as the NHL's best defenceman, beating Zdeno Chára of the Boston Bruins and Shea Weber of the Nashville Predators.

[18] The Senators made the 2013 Stanley Cup playoffs but were eliminated by Pittsburgh in the Eastern Conference Semifinal, with Karlsson registering one goal and seven assists in ten games.

On 2 October 2014, the Senators organization announced that Karlsson would serve as the ninth captain in the team's modern history, replacing the recently-traded Jason Spezza.

[22] On 24 June 2015, it was announced Karlsson won his second Norris Trophy, beating out fellow nominees Drew Doughty and P. K.

[23] Karlsson appeared in all 82 games for the third-straight season during the 2015–16 season and led the league in assists with a career high 66 assists and set a career high in points (82), finishing fourth in the league in scoring alongside San Jose Sharks forward Joe Thornton.

[31] Karlsson's performance continued into the 2017 playoffs, helping the Senators reach the Eastern Conference finals, the first time the team had done so since 2007.

Although the Senators would be eliminated by the Pittsburgh Penguins in seven games losing the deciding seventh game in double overtime, one win and goal short of reaching the Stanley Cup Finals, Karlsson was praised for his performance during the Senators' playoff run and how he continued playing despite suffering two hairline fractures in his left heel.

[34] Shortly after the Senators were eliminated from the playoffs, Karlsson had surgery to repair torn tendons in his left foot, resulting in him missing the beginning of the 2017–18 season.

[42] After a slow start to the 2018–19 season, Karlsson became the fifth defenceman in league history to have at least one assist in 14 consecutive games following a 7–2 victory over the Edmonton Oilers on 8 January 2019.

[43] On 23 December, Karlsson was suspended for the first time in his career for two games for an illegal check to the head of Los Angeles Kings player Austin Wagner.

[58][59] During the season, Karlsson also set an NHL record for defencemen by scoring or assisting on 43.35 percent of San Jose's total goals (101 of 233, excluding shootout-deciding goals),[60] while also setting a new Sharks franchise record for points in a season by a defenceman (previously held by Brent Burns) with 101.

Pittsburgh also sent a 2025 2nd round draft pick, defenseman Jeff Petry, goaltender Casey DeSmith and forward Nathan Legare to Montreal.

[62] Karlsson's performance has been widely acclaimed by current and former ice hockey players, head coaches and the media.

Karlsson tied for fourth in team scoring with Senators teammate Daniel Alfredsson at the 2012 World Championship with seven points and led all Swedish defencemen in that category.

On 21 February 2014, Karlsson's scored a powerplay goal in the semifinal against Finland to earn Sweden a spot in the gold medal final against Canada.

[citation needed] Karlsson declined an invitation to play for Sweden at the 2015 World Championship due to an undisclosed injury.

[98][99] On 12 June 2018, Karlsson's wife filed a protection order against Monika Caryk, girlfriend of Senators' teammate Mike Hoffman, for harassment both before and after the passing of their son.

The deposition revealed that wives and girlfriends of several players associated with the Senators and other organizations had contacted Caryk privately before the matter went public, admonishing her for her continued and increasing hostility towards the Karlssons.

[101] Later that year, Karlsson and his wife organized the charity "Can't Dim My Light" to raise funds and awareness about bullying in schools.

[102] Karlsson's childhood idols included Nicklas Lidström, Daniel Alfredsson, Mats Sundin and Peter Forsberg.