One of the most significant historical events in Villahermosa's history is the establishment of the city itself by the Spanish in 1564. Originally named Villa Hermosa de San Juan Bautista, the city was founded by the Spanish explorer Diego de Quijada. This event marked the beginning of Spanish influence in the region, which would have lasting effects on its culture, economy, and society.

The Spanish conquest of the Tabasco region was part of the larger effort to colonize Mesoamerica. Before the arrival of the Spanish, the area was inhabited by various indigenous groups, including the Olmecs, Mayans, and Chontals. These groups had rich cultures and complex societies, as evidenced by the archaeological remains found in the region.

When Diego de Quijada arrived in what is now Villahermosa, he encountered resistance from the indigenous populations. However, the superior military technology and strategic alliances with other indigenous groups allowed the Spanish to establish control over the area. The founding of Villa Hermosa de San Juan Bautista was a strategic move to secure Spanish dominance in the region and facilitate the exploitation of its resources.

Under Spanish rule, Villahermosa became an important administrative and commercial center. The city was strategically located along the Grijalva River, making it a key point for trade and transportation. The Spanish introduced new agricultural practices, crops, and livestock to the region, which transformed the local economy. They also imposed their religion, language, and customs on the indigenous population, leading to significant cultural changes.

The establishment of Villahermosa also marked the beginning of a long period of conflict and resistance. The indigenous populations did not easily accept Spanish rule, and there were numerous uprisings and rebellions over the years. These conflicts were often brutal, with significant loss of life on both sides. However, they also led to the development of a unique cultural blend as indigenous and Spanish traditions merged over time.

One of the key figures in the history of Villahermosa is Juan Bautista de Mora, who played a crucial role in the early development of the city. As one of the city's first mayors, he was responsible for implementing many of the administrative and infrastructural changes that helped Villahermosa grow. His leadership was instrumental in establishing the city's early institutions and ensuring its survival in a challenging and often hostile environment.

The legacy of the city's founding can still be seen in Villahermosa today. The city's layout, architecture, and cultural practices reflect its Spanish colonial past. Many of the historical buildings from the colonial period have been preserved and are now important cultural landmarks. The city's history is also celebrated in its museums and cultural institutions, which keep the memory of these early events alive for future generations.