Founded as Santa Cruz in 1555 by Juan Rodriguez Monjaraz, the then governor of the region, the city is known for First Cry of Independence and the population's efforts in the movement to separate Panama from Spanish power in November 1821.

A yearly festival is hosted to celebrate the anniversary of the beginning of Panama's war for independence, which started in La Villa de los Santos.

José Higinio Durán, the Catholic bishop of Panama, and Julián Chávez, the mayor of the city, were two individuals who called for Panama's independence.

According to local tradition, a woman born to slave parents named Rufina Alfaro participated in the occupation of Spanish military outposts in the town, although this is disputed.

This article about the geography of Los Santos Province is a stub.