The German started from pole and led the majority of the laps in a largely processional affair at the Autodromo Hermanos Rodriguez circuit.
He took victory by just over one second from Envision driver and fellow front-row starter Buemi, as 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, is under investigation for a technical infringement.
Wehrlein maintained his advantage from the pole at the start, while Buemi took to the inside line to prevent Maximilian Guenther from overtaking into Turn 1, with Cassidy, Mitch Evans, and Jake Hughes maintaining positions off the line.
The first of two Attack Mode activations came as early as lap three for the leaders, 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 attention 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.
But the race was neutralized on lap nine after Buemi’s Envision team-mate, Robin Frijns, lost control and made heavy contact with the barrier on the exit of T18.
The Dutchman had been trying to recover ground after struggling to get off the line due to a technical problem, and a safety car was deployed to recover his stranded machine, which had been left across the track.
After three laps under caution, and at the earliest opportunity, Buemi took his remaining Attack Mode and dropped to second, with Cassidy eventually moving up to third as Guenther did the same on lap 15.
By this point, the top nine drivers had used both activations, with Wehrlein holding a lead of almost a second from Buemi, with Cassidy and Guenther in close proximity.
Evans in fifth had started to gradually drop back, though, and the Jaguar driver came under pressure from the DS Penske of Jean-Eric Vergne, who had jumped Hughes in the Attack Mode activation phase.
Evans fell to more than 4s behind Guenther and was something of a cork in the bottle for Vergne, Hughes, Stoffel Vandoorne, Dennis, and Norman Nato behind.
Despite running nose-to-tail for the second half of the race, which was extended to 37 laps due to the earlier safety car, the top 10 positions remained unchanged until the chequered flag.
Oliver Rowland took 11th on his return with Nissan from team-mate Sacha Fenestraz, the pair heading Edoardo Mortara (Mahindra), Sam Bird (McLaren), and Nyck de Vries (Mahindra) on his Formula E return.
Jehan Daruvala, on his first race in Formula E with Maserati MSG, was 16th ahead of Abt Cupra’s Nico Muller and ERT’s Dan Ticktum.
As well as Frijns, other retirements included Porsche’s Antonio Felix da Costa, who damaged his suspension on lap three after contact with Muller into Turn 3 – an incident that will be investigated after the race.
Muller’s team-mate Lucas di Grassi was an opening lap retirement after suffering brake problems, while Sergio Sette Camara was unable to start due to technical issues with his ERT machine.
