Final answer:
The Pueblo Revolt in 1680 caused the death of over four hundred Spaniards and forced the survivors to move towards Mexico.
Step-by-step explanation:
The event that caused the death of over four hundred Spaniards and forced the remaining settlers to move south towards Mexico was the Pueblo Revolt in 1680. This coordinated uprising by the Pueblo people significantly impacted the Spanish presence in New Mexico. The Spaniards saw over four hundred of their people killed and the survival of around two thousand settlers became dependent on retreating toward Mexico. However, by 1692, the Spanish found an opportunity to recapture their territorial control despite initially ascribing the Pueblo victory to the work of the Devil. The impact of the Spanish colonization, including the Spanish invasion under Hernando Cortez and diseases such as smallpox, had already caused a drastic decline in the indigenous population throughout the Americas.