Verstappen started behind pole-getter Charles Leclerc and Ferrari teammate Carlos Sainz but got a better start than both, sandwiching himself between the red cars on the long run down to the first corner.
Sainz dropped back into third, opening space on the left side of the circuit for the surging Pérez, who had got the best launch of the lot from fifth.
It gifted the Mexican a chance to sweep around the outside of all three cars to take an unlikely lead in much the same way Verstappen had done to the Mercedes teammates in 2021.
But Pérez attempted to claim the corner before he was fully past Leclerc immediately to his right. The pair made heavy contact that sent the Red Bull Racing driver airborne and into the run-off zone.
His car was badly damaged, and though he was able to limp back to pit lane, the team could do nothing to get him back into his home race, breaking the hearts of more than 100,000 fans inside the Autodromo Hermanos Rodriguez.
“Being two times in a row on the podium, I just wanted to give it all. I went totally for it,” Pérez explained to British television. “I wasn’t expecting Charles to be in the middle… I think simply there was no room for three cars. It was a total racing incident.”
Verstappen escaped the incident unscathed and was able to sprint away to a dominant margin of more than 17 seconds by mid distance.
Leclerc was tenacious behind him despite damage to his front wing, but the battle for third was raging.
Daniel Ricciardo, who qualified a superb fourth for AlphaTauri, had held off Lewis Hamilton in the faster Mercedes for the first 11 laps before the Briton snuck through, and an early pit stop jumped Hamilton past Sainz and set his sights on second place.
But a big crash for Kevin Magnussen through the fast esses neutralised the race. The Haas driver’s car suffered a rear suspension failure through turn 8, spitting him at high speed into the wall.
The Dane was unhurt, but a red flag to repair the barriers reset the race.
Verstappen had little trouble re-establishing a healthy lead, and with no pit stops yet to make, he cruised home to a 13-second victory.
“It’s been another incredible season,” Verstappen said, reflecting on his 16th win, the most of any driver in a single season in F1 history. The win also drew the Dutchman level with Alain Prost on 51 Formula One victories.
“The car has been unbelievable to drive in most places. When you as a team work really well together and you try not to make too many mistakes over the whole season, then you can achieve something like this,” Verstappen added.
Hamilton clung to the back of Leclerc at the red flag restart, having chosen the faster but more delicate tyres in the hope of making a rapid move.
It took five laps of siege and two wheels edging the grass down the main straight to barge through, and in the clear air a long way behind Verstappen he was able to massage his tyres to the finish.
“The team did a great job I think with strategy,” he said. “A great result for the team, really proud of everyone.’
The result shrinks Hamilton’s gap to Pérez for second in the drivers championship to just 20 points with three rounds remaining.
Ferrari had hoped Leclerc’s choice of the slower but more durable hard tyres would swing momentum back towards him in the final laps, but the red car lacked the pace of the Mercedes, leaving the Monegasque with third ahead of Sainz in fourth.
The battle for fifth was a three-way fight between Ricciardo, George Russell and Lando Norris.
Russell jumped Ricciardo off the line at the red flag standing restart, but neither could hold back the charging Norris, who recovered from 17th on the grid to snatch the position from both.
The Briton had qualified well out of position after butchering his sole lap in Q1, but pre-race expectations that his McLaren had potential race-winning pace held true, with the 23-year-old hauling himself through the field late with a series of precision overtakes on some of the field’s heaviest hitters.
Russell faded late and only just held off Ricciardo, the pair finishing sixth and seventh, while Oscar Piastri finished eighth in his damaged McLaren, having taken hits at the start of the race and in a duel with Yuki Tsunoda that saw the pair twice make contact before the Japanese driver spun himself out of the race.
Thai driver Alex Albon drove a strong race from 14th to ninth for another two points for Williams ahead of Esteban Ocon in 10th.