Not much is known about the catacombs' early history. According to Ayauhtéotl, the site was once the location of a great battle fought long before, which apparently took the lives of many of the undead encountered in the tombs.Seth went to the Catacombs several months later. He took the Aztec Mask, making the Undead rise again, including John Marston.
The entrance to the Catacombs can be found in the spectator bleachers alongside the bullfighting ring behind the Escalera Mansion. The Catacombs weave and turn around underneath Escalera.
They are notably of Aztec design, featuring large blocks of stone lining the walls and ancient runes covering them. Many different rooms and corridors feature the different Undead types. Also introduced in this area is a new enemy - Mummies - which fall from the walls while John ventures down. The further the player ventures into the Catacombs, the narrower the corridors become, eventually leading into a main room with four supporting pillars and an altar; where the Aztec Mask once lay before being taken by Abraham Reyes.
- During the mission "A Civilized Man", John enters the catacombs at the insistence of and accompanied by a woman who is later revealed to be an ancient Aztec goddess.
- The Semi-auto Shotgun can be found in the catacombs.
- Upon completing Undead Nightmare, if the player returns to the catacombs the entrance will be boarded up and unavailable to be entered. This is also true if the player attempts to enter the catacombs before the mission "A Civilized Man".
- The battle that Ayauhtéotl says took place was likely fought between Spanish Conquistadors and Aztecs, given the age and architecture of the catacombs. Also, the Shield of Castille, a Spanish symbol, appears at the entrance.