Perez, already under pressure for a run of poor form, tried to pass the Ferrari around the outside but their wheels made contact, with the Red Bull pitched into the air and on to the run-off with sidepod damage while Leclerc continued.
The Mexican got his car back to the pits and stayed in it for a long while before getting out, hitting the steering wheel in frustration.
This year's race has drawn a record 400,639-strong attendance, most of them coming to cheer on a home hero who said before the weekend that it was his most important race of the season.
Perez had stood proudly at the singing of the national anthem and the crowd at the Autodromo Hermanos Rodriguez had yelled his name before the nightmare unfolded and tears replaced the cheers.
The Red Bull driver had started fifth and made a quick getaway, with triple champion Max Verstappen going past Leclerc on the inside to take the lead as the Ferrari was caught in a sandwich.
While Perez will remain second in the championship standings after starting the race with a 39-point advantage over Mercedes's Lewis Hamilton, the blank will fuel further speculation about his future at Red Bull.
The team and Verstappen, who is chasing a record 16th win of the season, have already won both championships.