Climate change predictions suggest that the aquatic environment in the Mekong River Delta will change significantly over the next several decades, primarily manifested as higher temperatures with extensive marine incursions. As such, this study was conducted to evaluate the effects of sublethal levels of temperature and salinity and their interaction (TxS) on growth rates and physiological responses of tra catfish (Pangasianodon hypophthalmus), a significant culture species in Vietnam. We aimed to assess the levels of tolerance and acclimation ability when individuals were exposed to simulated predicted conditions of climate change on fish farms in the Mekong Delta in southern Vietnam. Fish were acclimated over an appropriate time frame and then distributed randomly to nine treatment groups across combinations of three temperatures (25, 30, 35 °C) and three salinities (0, 6, 12‰). Results showed that temperature, salinity, and TxS all had significant effects on individual growth rate and feed conversion efficiency, with fish reared at 35 °C and 6‰salinity displaying the best growth (P< 0.05), while also producing significantly superior FCR values in comparison with the majority of other treatments. Tra catfish were able to acclimate to changes in water temperature and salinity, by increasing their RBC and Hb concentrations. Internal osmotic pressure was salinity-dependent with significantly higher pressure seen when fish were exposedto12‰conditions when compared with other treatments, irrespective of temperature. Interaction effects among temperature, salinity, and sampling time were identified for plasma glucose concentration, cortisol, and IGF-1 levels. Glucose, cortisol, and IGF-1 levels increased over the early phase of the experiment, then declined and stabilized for the remainder of the experiment. These results together suggest that moderate increases in water temperature and salinity do not impose a significant stress the tra used in this experiment. Therefore, it appears that the tra catfish industry is unlikely to suffer short-term negative impacts under predicted climate change scenarios, and performance may actually improve in conditions of 35 °C-6‰.