INTRODUCTION: Major depressive disorder (MDD) is a highly prevalent psychiatric condition worldwide, and it is the leading cause of disability globally. Turmeric, an aromatic perennial herb widely used in traditional Asian medicine and cuisine, contains curcumin, which has several biological effects, including a pseudoantidepressant effect. However, curcumin's low bioavailability limits its effectiveness. This study evaluated nanocurcumin (NCUR) effects on depressive-like behaviors and examined serum BDNF and serotonin levels in a chronic stress model in rats. Behavioral assessments and biochemical indicators elucidated NCUR's antidepressant-like properties. METHODS: In this experimental study, 30 adult male rats were randomly divided into six groups and exposed to unexpected chronic mild stress (UCMS). The groups included: control (CG), stress control (SCG), fluoxetine (FLU) treatment (20 mg/kg), and three NCUR doses (20, 40, and 80 mg/kg). Before UCMS exposure, rats underwent a sucrose preference test (SPT). Depressive behaviors were then assessed using the open field test (OFT), forced swimming test (FST), and tail suspension test (TST) on days 27 and 28. Blood samples were collected on day 28 to measure serum Brain derived neurotrophic factor (BDNF) and serotonin levels using enzyme-linked immunosorbent assay (ELISA). RESULTS: NCUR treatment significantly alleviated depressive-like behaviors in stressed rats. The sucrose preference index of the SCG decreased after 26 days of stress, while NCUR (all doses) and FLU reversed this effect. In the FST and TST, immobility time was significantly reduced in the NCUR and FLU groups compared to the SCG (p <
0.05). The OFT also showed that the SCG had significantly fewer crossings compared to treated groups (p <
0.05). Additionally, NCUR treatment significantly increased serum BDNF and serotonin levels compared to the SCG. CONCLUSIONS: This study demonstrates that NCUR exerts antidepressant-like effects, improving depressive behaviors and increasing BDNF and serotonin levels in rats exposed to chronic stress. NCUR may offer a promising alternative for the treatment of MDD.