Abstract: In archipelagic countries, aquaculture of tilapia is commonly affected by variable and fluctuating salinities associated with tidal flow, salt water intrusions, rainfall and season which can cause stress to the species and affects the overall production. In the present study, the effect of salinity exposure on stress response and amino catabolic enzymes of Nile tilapia Oreochromis niloticus was investigated. Seventy two Nile tilapia Oreochromis niloticus (size: 44.57±0.48 g) were distributed to 6 units of 60 L plastic tanks to constitute the two salinity exposure treatments run in triplicates. The experimental fish were exposed to two salinities at 15 and 30 ppt for a period of 7 days. Results indicated that after 24 h exposure stressors plasma cortisol and blood glucose were found to be significantly elevated (p<0.01) at 30 ppt as compared to those exposed at 15 ppt. This elevated cortisol and glucose levels persist at the higher treatment until the 7th day of exposure. Enzymes involved in the amino acid catabolism for energy production were found elevated in response to salinity stress. Serum ALT and AST were significantly higher (p<0.01) at 30 ppt as compared to the control. Survival was negatively affected by higher salinity level (p<0.01). This study demonstrates that exposure to higher salinity could result in elevated stress responses and amino enzymes catabolism of Nile tilapia. The present results add to the understanding of the physiological responses of tilapia on salinity stress and would be helpful in formulating strategies to optimize the aquaculture of this species in environments with fluctuating patterns of salinity.