The German was the dominant force in the race at the Autodromo Hermanos Rodriguez circuit after starting from pole and leading the majority of the laps in a largely processional affair.
He eventually took victory by just over one second from Envision driver and fellow front-row starter Sebastien Buemi, as Nick Cassidy took a podium on his Jaguar debut.
Reigning champion Jake Dennis could only manage ninth, having suffered a difficult qualifying session which left the Andretti driver 14th on the grid, and like Wehrlein remains under investigation for a technical infringement.
Wehrlein maintained his advantage from pole at the start, while behind, Buemi took to the inside line to prevent Maximilian Guenther from overtaking into Turn 1 with Cassidy, Mitch Evans and Jake Hughes maintaining position off the line.
The first of two Attack Mode activations came as early as lap three for the leaders, with Wehrlein taking two minutes and rejoining behind Buemi, but a lap later the positions were reversed again, with Buemi taking six minutes of Attack Mode.
By lap six, Wehrlein had taken the remaining six minutes of his Attack Mode and once again only lost one position to Buemi before heavily pressuring the Envision driver for the lead.
The front two had started to gap Guenther behind, who had the close attentions of Cassidy to deal with as the Kiwi was the only other front runner apart from Wehrlein to have used both Attack Modes by this point.
Source: Autosport