The leopard coral grouper (Plectropomus leopardus) is a commercially significant tropical marine species. With the ongoing effects of global climate change, increasing attention has been focused on leopard coral grouper’s susceptibility to extreme cold weather. This study investigates the effects of acute cold exposure and temperature recovery on the liver of P. leopardus. Histological observations and enzyme activity assays revealed that temperature fluctuations caused significant disruptions to normal liver physiology, including lipid accumulation and alterations in antioxidant levels. Transcriptomic analysis of liver tissue identified 2744 differentially expressed genes (DEGs) across three experimental groups: 25 °C (control), 13 °C (cold exposure), and rewarming at 25 °C (R-25 °C). Functional enrichment analysis revealed that these DEGs were significantly associated with biological processes such as lipid metabolism and antioxidant defense, as well as pathways related to metabolism, fatty acid biosynthesis, and ferroptosis. Furthermore, dynamic regulation of lipid metabolism, immune responses, and oxidative stress pathways was observed in response to both cold stress and rewarming. Notably, several redox-related DEGs were identified, and their interactions with lipid metabolism were further explored. Additionally, representative DEGs associated with antioxidants and lipid metabolism, such as got1, gpx1a, gpt, and g6pcla.2, were validated by qRT-PCR and fluorescence in situ hybridization (FISH). Taken together, this study provides a systematic analysis of the effects of acute cold exposure and temperature recovery stress on the liver of the leopard coral grouper, laying the groundwork for further research on the temperature stress responses in teleost species.