Chronic heat stress can have detrimental effects on the survival of fish. This study aimed to investigate the impact of prolonged high temperatures on the growth, antioxidant capacity, apoptosis, and transcriptome analysis of Hong Kong catfish (Clarias fuscus). By analyzing the morphological statistics of C. fuscus subjected to chronic high-temperature stress for 30, 60, and 90 days, it was observed that the growth of C. fuscus was inhibited compared to the control group. The experimental group showed a significant decrease in body weight and body length compared to the control group after 60 and 90 days of high-temperature stress (p < 0.05, p < 0.01). A biochemical analysis revealed significant alterations in the activities of three antioxidant enzymes superoxide dismutase activity (SOD); catalase activity (CAT); glutathione peroxidase activity (GPx), the malondialdehyde content (MDA), and the concentrations of serum alkaline phosphatase (ALP); Aspartate aminotransferase (AST); and alanine transaminase (ALT) in the liver. TUNEL staining indicated stronger apoptotic signals in the high-temperature-stress group compared to the control group, suggesting that chronic high-temperature-induced oxidative stress, leading to liver tissue injury and apoptosis. Transcriptome analysis identified a total of 1330 DEGs, with 835 genes being upregulated and 495 genes being downregulated compared to the control group. These genes may be associated with oxidative stress, apoptosis, and immune response. The findings elucidate the growth changes in C. fuscus under chronic high temperature and provide insights into the underlying response mechanisms to a high-temperature environment.