Vegas, which has won eight of its past nine home games, leads the Edmonton Oilers by two points for first place in the Pacific Division. The Oilers defeated the Dallas Stars 2-1 in overtime on Tuesday.
Mackenzie Blackwood made 29 saves for the Devils (26-28-12), who lost in regulation for the first time in seven games (4-1-2). Blackwood lost in regulation for the first time in eight starts (6-1-1).
"It was a disappointing effort," Devils coach Alain Nasreddine said. "If you look at our game in general, our execution was atrocious. Our level of focus wasn't great, and our execution cost us a lot of problems."
It was the final game of a five-game road trip for the Devils, who finished 2-1-2.
"I think it's more on us, to be honest. We just didn't execute or make any plays tonight," Devils forward Travis Zajac said. "For whatever reason, we didn't make many tape-to-tape plays. [It was] one of those games where we couldn't find a rhythm."
Pacioretty scored 45 seconds into the second period for a 1-0 lead. Karlsson made a no-look, backhand pass from the Vegas blue line to Pacioretty, who scored short side from the left circle.
Karlsson extended the lead to 2-0 with his 100th NHL goal 37 seconds into the third period on a one-timer from Nicolas Roy.
"I won't think about it too much, but maybe after I'm done it'll be a nice milestone [to look back on]," Karlsson said.
Ryan Reaves made it 3-0 at 8:49.