Endothermy has independently evolved in several vertebrate lineages but remains rare among fishes. Using an integrated approach combining phylogenomic and ecomorphological data for 1051 ray-finned fishes, a time-dependent evolutionary model, and comparative genomic analyses of 205 marine vertebrates, we show that ecological interactions with modern cetaceans coincided with the evolution of endothermy in ray-finned fishes during the Eocene-Miocene. This result is supported by evidence of temporal and geographical overlap between cetaceans and endothermic fish lineages in the fossil record, as well as correlations between cetacean diversification and the origin of endothermy in fishes. Phylogenetic comparative analyses identified correlations between endothermy, large body sizes, and specialized swimming modes while challenging diet specialization and depth range expansion hypotheses. Comparative genomic analyses identified several genes under selection in endothermic lineages, including (involved in fatty acid metabolism) and (associated with development). Our findings advance the understanding of how ecological interactions and genomic factors shape key adaptations.