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Natural products and traditional remedies have become more popular over the years since they have less harmful side effects and are considered environmentally friendly. In this study we aimed to investigate the potential of Gynura procumbens extract (GPE), a well-known traditional medicinal plant extract, on the stress modulation of Oreochromis niloticus (Nile tilapia). Four different experimental groups: control, stress, prevention, and treatment were monitored for 12 weeks. Hydrocortisone (0.01% of body weight) was incorporated with the feed to induce the stress response in stress, prevention and treatment groups. Feed was also supplemented with 0.15% GPE of body weight for the prevention and treatment groups. Cortisol concentration was reduced significantly in the prevention (1870.52 pg/mL; p = 0.006) and treatment (2925.91 pg/mL; p = 0.002) groups than the stress group (7614.22 pg/mL). The result is substantiated by significant decrease in blood glucose level in prevention (29.5 mg/dL; p = 0.002) and treatment (31.5 mg/dL; p = 0.006) groups, compared to stress group (47.33 mg/dL) at the end of the experiment. Considering the current finding, we can conclude the GPE has potential to be used as therapeutic option for stress regulation however there is a room for further detailed study to understand the in-depth mechanism.