William Karlsson and Alexander Holtz scored, and Ilya Samsonov made 19 saves for the Golden Knights (17-7-3), who were coming off a 1-0 win against the Edmonton Oilers on Tuesday and have won six of eight (6-1-1). Jack Eichel, Tomas Hertl and Victor Olofsson each had two assists.
"(Tuesday) night, it was the third period where we kind of bent but didn't break," Vegas coach Bruce Cassidy said. "I thought we had a better third period tonight, able to extend the lead and really limit their damage, so a lot of that is puck management, making them go 200 feet. That way, you get to use everybody, and nobody is fatigued."
Jackson LaCombe scored, and John Gibson made 29 saves for the Ducks (10-11-3), who had won two of three.
Anaheim forward Trevor Zegras had to be helped off the ice with a lower-body injury 40 seconds into the second period and did not return.
Zegras, 23, missed 51 games last season with a groin injury and a broken ankle.
Ducks coach Greg Cronin did not have an update after the game, but said his absence already had an impact.
"What happens is you’re down a forward and you rotate different bodies," Cronin said. "The chemistry that you had through your lines, which have been consistent for a couple games, gets disrupted, but it happens. It’s hockey and guys get hurt."
Karlsson gave the Golden Knights a 1-0 lead at 16:26 of the first period. Nicolas Hague took a wrist shot from above the left circle that glanced off the skate of Karlsson and was saved by Gibson. The rebound came out to the side of Gibson and Karlsson spun away from Anaheim defenseman Cam Fowler before sweeping the puck into the open net.