[3] Of the municipality's population, 3,655 (5.22%) spoke an indigenous language, primarily Popoluca, followed in numbers by Zapotec.

In addition to the seat, the municipality's largest other communities are Corral Nuevo and Dehesa.

Conquistadores Gonzalo de Sandoval and Hernan Cortés passed through Acayucan on the route from Tuxtepec to Tenochititlan.

In 1580 it was part of the ′′Villa de Espíritu Santo′′ (Coatzacoalcos); when this was wiped out by pirates, Ayayucan became the seat of the Alcaldía mayor.

[4] In May 2020, Francisco Navarette Serna, presumed drug chieftain responsible for the February 2016 murders of five young people from Acayucan between 16 and 27 years old, was killed at a party at the height of the COVID-19 pandemic in Mexico.