The Zapotecs probably arrived in the central valleys of Oaxaca around the second century CE, when much of what is now the Tlacolula Valley was covered by a lake. The chronicler Fray Juan de Torquemada believed they came from a region called Panuco, establishing themselves first at Tule before founding a dominant settlement at Teotitlan del Valle. Over time, the early populations drained the lake and built a network of communities across the newly exposed land. The original Zapotec name for Tlacolula was Guillbaan - "village of the burials" - and tradition holds that the city was first founded at what is now the archaeological site of Yagul, a former city-state first occupied around 500-100 BC. The visible ruins there date mostly to 1250-1521 AD, when Yagul served as the capital of a Postclassic city-state. It was still inhabited at the time of the Spanish Conquest; afterward, its population was relocated to modern Tlacolula, where their descendants live today.

The Spanish established Santa Maria de la Asuncion Tlacolula formally in 1560, and the Church of La Asuncion went up the following year as a Dominican mission. From the outside, it resembles other Dominican churches in the Central Valleys - solid stone, restrained in ornament, built to last in earthquake country. But step inside and turn into the Capilla del Senor de Tlacolula, and restraint vanishes. The chapel is an explosion of Baroque decoration, every surface carved, gilded, and layered with ornamentation that seems to multiply the longer you look. At its center is a crucifix called the Senor de Tlacolula, to which many miracles have been ascribed over the centuries. The feast of the Christ of Tlacolula, held on the second Sunday of October, lasts five days and is celebrated with Masses, processions, folk dances, fireworks, and - remarkably - the Mixtec version of the Mesoamerican ball game, connecting a Catholic festival to a tradition that predates Christianity on this continent by millennia.

The Tlacolula Valley is home to over 60,000 people, many of them Zapotec speakers, but the community extends far beyond the valley itself. Economic pressures have driven significant migration to the United States, with Tlacolula residents congregating specifically in the Venice Beach area of southern California. The concentration is remarkable: so many families from the valley have settled there that Zapotec is the mother tongue of roughly thirty percent of schoolchildren in certain neighborhoods. Many Zapotec-speaking immigrants from Tlacolula work in the boardwalk stalls or as cooks, waiters, and kitchen staff in the upscale restaurants and hotels of nearby Santa Monica. This transnational community maintains strong ties to the valley, sending remittances home and returning for festivals. Meanwhile, the language itself is under pressure at both ends. In April 2014, linguist Brook Danielle Lillehaugen and students from Haverford and Swarthmore Colleges visited Tlacolula to present an online Tlacolula Valley Zapotec talking dictionary to local leaders. At that time, an estimated 100 elderly speakers of this specific Zapotecan variety remained.

Beyond the Sunday market and the Baroque chapel, the municipality holds something of global significance: approximately one hundred caves and rock shelters scattered through the Tlacolula Valley that document one of the most consequential transitions in human history. These caves contain prehistoric paintings and, more importantly, evidence of the shift from hunting and gathering to sedentary agriculture through the domestication of corn and other plants. Mexico's National Institute of Anthropology and History - INAH - has worked to catalog and document the sites, recommending them for World Heritage status. The sites were inscribed on Mexico's Lista Indicativa in the 2000s, and UNESCO recognition followed in 2010. The nearby archaeological site of Yagul, excavated in the 1950s and 60s by archaeologists Ignacio Bernal and John Paddock, was declared a Natural Monument in 1998. Together, the caves and Yagul tell a story that spans from the earliest experiments in agriculture on the American continent through the rise and fall of Zapotec city-states to the Sunday morning bustle of a market that has not stopped for centuries.