In recent years, drugs have been identified as newly emerging and threatening pollution in aquatic and terrestrial ecosystems. Therefore, in this study, the effect of indomethacin on oxidative stress in Cyprinus carpio was investigated. In order to determine the LC50, fish were exposed to various concentrations (30. 60. 100, 150, 250, and 400 mg/l) of indomethacin and daily mortality were recorded during 96 hours. In the next step, fish were exposed to various concentrations of indomethacin (0, 0. 01, 0. 02, 0. 05, and 0. 1 time of LC50 96h) in five treatments including T1 (control), T2 (3. 3), T3 (6. 4), T4 (6. 6), and T5 (32. 8 mg/l) for 28 days. At the end of the experiment, antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPX), and malondialdehyde (MDA) were measured in the liver and gill. The lethal toxicity (LC50) of indomethacin was obtained for carp (328. 49 mg/l). GPX had higher activity in gill and liver in all treatments compared to the control group. MDA levels in liver in T4 and T5 groups and gill tissue in T3 and T4 groups showed a significant increase compared to the control group. Also, CAT had higher activity in liver and gill in T4 and T5 groups compared to the control group. Indomethacin leads to stress by increasing the production of reactive oxygen species and increasing lipid peroxidation, therefore, it is exposed to the antioxidant system of liver tissue and gills of fish and induces a response in the form of increased antioxidant enzyme activities. The results of this study demonstrated that the presence of indomethacin in an aqueous environment can influence the antioxidant status and health of the fishes.