After being selected by the Golden Knights in the 2017 NHL expansion draft, Karlsson has been one of the key points of the team offense, and helped Vegas reach the Stanley Cup Finals in their inaugural season.

In the 2011–12 season, Karlsson finished in 12th place in Allsvenskan scoring after recording 45 points in 46 games, the second-most on his team.

[7] Karlsson spent the 2017–18 season (Vegas' first in the NHL) centering a line with Reilly Smith and Jonathan Marchessault.

[13] Karlsson was also named a finalist for the Lady Byng Memorial Trophy for his high standard of play and sportsmanship.

[14] On 20 June, he was named the recipient of the trophy, becoming the first player since Wayne Gretzky to win an end-of-season award in their team's inaugural season in the NHL.

[17] Karlsson described his decision to sign a one-year contract as "betting on [him]self a little" and that he would use the subsequent season to prove that his 2018–19 production "was no fluke".

[19] By the 2022–23 season, Karlsson was one of six remaining original members of the Golden Knights, alongside Marchessault, Smith, Brayden McNabb, Shea Theodore and William Carrier.