Loss of megafauna, an aspect of defaunation, can precipitate many ecological changes over short time scales. We examine whether megafauna loss can also explain features of lasting ecological state shifts that occurred as the Pleistocene gave way to the Holocene. We compare ecological impacts of late-Quaternary megafauna extinction in five American regions: southwestern Patagonia, the Pampas, northeastern United States, northwestern United States, and Beringia. We find that major ecological state shifts were consistent with expectations of defaunation in North American sites but not in South American ones. The differential responses highlight two factors necessary for defaunation to trigger lasting ecological state shifts discernable in the fossil record: (i) lost megafauna need to have been effective ecosystem engineers, like proboscideans; and (ii) historical contingencies must have provided the ecosystem with plant species likely to respond to megafaunal loss. These findings help in identifying modern ecosystems that are most at risk for disappearing should current pressures on the ecosystems' large animals continue and highlight the critical role of both individual species ecologies and ecosystem context in predicting the lasting impacts of defaunation currently underway.