Otodontids include some of the largest macropredatory sharks that ever lived, the most extreme case being Otodus (Megaselachus) megalodon. The reasons underlying their gigantism, distribution patterns and extinction have been classically linked with climatic factors and the evolution, radiation and migrations of cetaceans during the Paleogene. However, most of these previous proposals are based on the idea of otodontids as ectothermic sharks regardless of the ecological, energetic and body size constraints that this implies. Interestingly, a few recent studies have suggested the possible existence of endothermy in these sharks thus opening the door to a series of new interpretations. Accordingly, this work proposes that regional endothermy was present in otodontids and some closely related taxa (cretoxyrhinids), playing an important role in the evolution of gigantism and in allowing an active mode of live. The existence of regional endothermy in these groups is supported here by three different approaches including isotopic-based approximations, swimming speed inferences and the application of a novel methodology for assessing energetic budget and cost of swimming in extinct taxa. In addition, this finding has wider implications. It calls into question some previous paleotemperature estimates based partially on these taxa, suggests that the existing hypothesis about the evolution of regional endothermy in fishes requires modification, and provides key evidence for understanding the evolution of gigantism in active macropredators.