Jujhar Khaira and Riley Stillman scored for the Blackhawks, who were 0-3-3 in their previous six games.
It was Fleury's first start against Vegas since being traded in the offseason. He has now beaten all 32 NHL teams in his career.
Fleury, who was with Vegas for its first four seasons in the league, has posted a 9-4-2 record across his past 15 games after starting the season with one win in his first eight appearances.
The 18-year veteran and three-time Stanley Cup champion was greeted by a tribute video before the game, which sent the announced crowd of 18,367 into a frenzy.
Ben Hutton scored the lone goal for Vegas, while Robin Lehner made 19 saves for the Golden Knights.
The game's three goal scorers had combined for two goals entering the game, and Khaira had both of them.
Hutton got his first goal of the season when he gathered the puck off a faceoff and fired it perfectly over Fleury's right shoulder into the upper left corner of the goal 5:17 into the game.
The Blackhawks tied it when Khaira shagged the puck off a bank pass, skated into the zone and fired a wrist shot far side and under Lehner's right arm at 4:38 of the second.
Chicago took the lead when Stillman's shot from the top caromed off Vegas center Brett Howden's knee and into the net with 5:39 remaining in the middle period.
Blackhawks: At Columbus on Tuesday night.
Golden Knights: Host Toronto on Tuesday night.