The F1 world champion held his nerve off the line to lead into Turn 1 from pole position, a grid slot which rarely produces race wins in the Mexican altitude.
Lewis Hamilton punished George Russell for going wide into the first corner, the younger of the Mercedes drivers having gone off in qualifying to deprive himself of pole, and he was then out of shape through the chicane as Sergio Perez nabbed ahead to take third place.
Verstappen struggled to shake Hamilton off his tail during the Red Bull’s first stint, despite taking the quicker, less durable soft tyre for the start while the Merc pair strapped on medium tyres.
By lap 24 of 71, the softs were giving way but Perez’s five-second pit stop dropped him back before Verstappen followed through for a cleaner tyre swap, and began to gain time on Hamilton with fresh mediums bolted on.
The 37-year-old champion, who said ahead of the weekend he is sticking around in F1 for some time yet, came in for hard tyres on lap 30 to go for a one-stopper.
Both Hamilton and Russell, who attempted to extend for a late set of softs before relenting to fall into line, complained of a lack of pace as Verstappen stretched out a ten-second gap in front.
Mercedes assured their drivers the hard tyres would come back as the mediums faded late on, as it became increasingly apparent Red Bull could also stretch their strategy out to a one-stop despite pre-race premonitions that a two-stopper would prove faster.
The mathematics of it all turned this race into one for the purists, the sector-by-sector times and triple decimals on the left of the screen holding the clues as to who will win - rather than furious, wheel-to-wheel battles.
The final third of the race saw Verstappen brush aside any worries over his strategy, continuing to put time on Hamilton as, despite a late virtual safety car for Fernando Alonso’s retirement, he cruised to a record 14th win of 2022 - the most a single driver has managed in a single season.