Rice bran extract (RBS) possesses a wide range of biological properties; however, its potential antidepressant effects and molecular mechanisms remain unclear. This study aimed to investigate the antidepressant effects of RBS in a mouse model of chronic stress (CS)-induced depression and anxiety and elucidate the underlying molecular mechanisms. Mice exposed to CS were administered RBS at different doses (250, 500, and 1000 mg/kg/body weight) for 5 weeks. The results demonstrated that RBS significantly improved depressive and anxiety symptoms, as evidenced by increased sucrose preference and reduced immobility time in behavioral tests. RBS supplementation also led to a reduction in the levels of adrenocorticotropic hormone, corticosterone, and corticotropin-releasing hormone in the serum of CS-exposed mice. Additionally, RBS downregulated the expression of glucocorticoid receptors and FK506 binding protein 5 in the prefrontal cortex and hippocampus. Furthermore, RBS supplementation led to reduced levels of serotonin, dopamine, and norepinephrine in the brain, while reducing the protein and mRNA expression of monoamine oxidase. The study further revealed that RBS activated the extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling pathways in both the prefrontal cortex and hippocampus. These findings highlight the potential antidepressant effects of RBS by modulating the hypothalamic-pituitary-adrenal axis, the monoaminergic system, and the ERK-CREB-BDNF signaling pathways. This study suggests that RBS could be a promising therapeutic approach for chronic stress-induced depression.