This study investigated the neuroprotective effects of nanophytosomal citral against chronic unpredictable mild stress (CUMS)-induced depression in mice, with exploration of potential mechanisms. Following six weeks of CUMS exposure, mice received either fluoxetine (20 mg/kg) or nanophytosomal citral (10, 20, or 50 mg/kg) via oral gavage three times weekly for three consecutive weeks. Behavioral changes were evaluated using the forced swimming test (FST), open field test (OFT), tail suspension test (TST), and sucrose preference test (SPT). The mRNA expression levels of TNF-α, IL-6, and BDNF were quantified using real-time PCR. Serum cortisol levels and oxidative stress markers were assessed using ELISA kits. CUMS significantly reduced SP and BDNF mRNA levels while increasing immobility time, serum cortisol levels, TNF-α and IL-6 mRNA expression, and enhancing oxidative stress through reduced antioxidant enzyme activity. Notably, all CUMS-induced alterations were significantly reversed following treatment with fluoxetine or citral nanophytosome (20 and 50 mg/kg). These findings collectively suggest that citral nanophytosome produces antidepressant-like effects in the CUMS model, potentially through mechanisms involving attenuation of oxidative stress and inflammation, along with restoration of BDNF expression.