In this study, we focused on the exceptionally large mammals inhabiting the Americas during the Quaternary period and the paramount role of body size in species ecology. We evaluated two main features of Pleistocene food webs: the relationship between body size and (i) trophic position and (ii) vulnerability to predation. Despite the large range of species sizes, we found a hump-shaped relationship between trophic position and body size. We also found a negative trend in species vulnerability similar to that observed in modern faunas. The largest species lived near the boundary of energetic constraints, such that any shift in resource availability could drive these species to extinction. Our results reinforce several features of megafauna ecology: (i) the negative relationship between trophic position and body size implies that large-sized species were particularly vulnerable to changes in energetic support; (ii) living close to energetic imbalance could favour the incorporation of additional energy sources, for example, a transition from a herbivorous to a scavenging diet in the largest species (e.g. Megatherium) and (iii) the interactions and structure of Quaternary megafauna communities were shaped by similar forces to those shaping modern fauna communities.