The larval phase of the fish life cycle has the highest mortality, particularly during the transition from endogenous to exogenous feeding. However, the transcriptional events underlying these processes have not been fully characterized. To understand the molecular mechanisms underlying mouth-opening acclimation, RNA-seq was used to investigate the transcriptional profiles of the endogenous feeding, mixed feeding and exogenous feeding stages of zebrafish larvae. Differential expression analysis showed 2172 up-regulated and 2313 down-regulated genes during this stage. Genes associated with the assimilation of exogenous nutrients such as the arachidonic acid metabolism, linoleic acid metabolism, fat digestion and absorption, and lipogenesis were activated significantly, whereas dissimilation including the cell cycle, homologous recombination, and fatty acid metabolism were inhibited, indicating a physiological switch for energy storage occurred during the mouth-opening stage. Moreover, the immune recognition involved in the antigen processing and presentation pathway was activated and nutritional supply seemed to be required in this event confirmed by qPCR. These results suggested the energy utilization during the mouth-opening stage is more tended to be reserved or used for some important demands, such as activity regulation, immune defense, and lipid deposition, instead of rapid growth. The findings of this study are important for understanding the physiological switches during the mouth-opening stage.