Diego de Mazariegos founded San Cristóbal as the Spanish regional base in 1528. Its Spanish citizens made fortunes from wheat, while the indigenous people lost their lands and suffered diseases, taxes and forced labor.

However, the church afforded some protection against colonist excesses. Dominican monks reached Chiapas in 1545, and made San Cristóbal their main base. The town is now named after one of them, Bartolomé de Las Casas, who was appointed bishop of Chiapas and became the most prominent Spanish defender of indigenous people in colonial times.

San Cristóbal was the Chiapas state capital from 1824 to 1892.

San Cristóbal remained relatively isolated until the 1970s, when tourism began to influence its economy. Recent decades have seen an influx of indigenous villagers into the 'Cinturón de Miseria' (Belt of Misery), a series of impoverished, violence-ridden, makeshift colonies around San Cristóbal's periférico (ring road). Many of these people are here because they have been expelled from Chamula and other communities as a result of internal politico-religious conflict. Most of the craft sellers around Santo Domingo church, and the underage hawkers around town, come from the Cinturón de Miseria.

San Cristóbal was catapulted into the international limelight on January 1, 1994, when Zapatista rebels selected it as one of four places in which to launch their revolution, seizing and sacking government offices in the city center before being driven out within a few days by the Mexican army.

Zapatista insurgency continues. In 2006, the rebels returned to San Cristóbal to launch 'The Other Campaign', a campaign in which rebels toured Mexico to spread their message.

Despite political and social tensions, San Cristóbal's future as a magnet for travelers looks secure, with a burgeoning tourist sector and cultural scene, a booming property market and a growing middle class.