In addition, the name of the municipality includes the Spanish ending indicating locality "ejo."

The area's Spanish settlers were subject to continuous attacks by Chichimec forces during the early colonial period.

In 1860, republican troops led by General Ignacio Zaragoza defeated Leonardo Márquez near the town as he fled from Tepatitlán.

In 1887, Zapotlanejo was part of the fourth department of the first canton of the state.

[4] The Dos Lunas Tequila brand is produced just outside town.