Cold stress is detrimental to physiological fitness and can lower the survival rate, especially for the fishes with low ability of cold-tolerance. To further understand the coping mechanism on cold stress, we applied an integrated metabolomic and transcriptomic analyses to reveal the hepatic metabolic responses when cold-sensitive red-tail catfish and cold-tolerant longsnout catfish were exposed to lower temperature by a programmed cooling method. Differentially expressed genes (DEGs) and significantly different metabolites (DMs) related to lipid synthesis and metabolism were identified from comparative metabolomic and transcriptomic data, respectively. The results indicate that the two catfish species show significantly different responses to the cold stress. Synthesis and metabolism of related lipids can be mobilized quickly and efficiently to compensate for the integrity and maintain the fluidity of cell membranes in the early cooling stage in longsnout catfish, but not in red-tail catfish. The anti-oxidative and apoptosis system can be activated positively in the middle and late cooling stages in longsnout catfish, but it is inhibited in red-tail catfish, which may be the potential reason for red-tail catfish death. Therefore, this study provides key information for understanding low-temperature tolerance mechanisms in catfish.