Depression is emerging as a social and health-related issue worldwide. Rice bran possesses a variety of biological properties; however, its potential efficacy and molecular mechanisms in depression remain unclear. This study investigated the antidepressant effects of rice bran supplement (RBS) in a mouse model of chronic restraint stress (CRS)-induced depression. RBS was administered to mice subjected to CRS for 5 weeks. RBS improved depressive symptoms in CRS-exposed mice, as evidenced by increased sucrose preference and reduced immobility time. It reduced hypothalamic-pituitary-adrenal (HPA) axis-related hormones. Additionally, RBS downregulated the glucocorticoid receptor (GR) pathway and upregulated the ERK-CREB-BDNF pathway in the prefrontal cortex and hippocampus. Furthermore, RBS increased neurotransmitter levels and decreased monoamine oxidase levels in the brain. Molecular docking analysis indicated that γ-oryzanol (ORY) interacts with GR. Moreover, ORY inhibited GR activity in GR-transfected HEK293T cells. The effects of ORY were not significantly altered by treatment with GR antagonist mifepristone or GR siRNA, suggesting ORY functions as a GR antagonist. Additionally, ORY administration improved depressive behaviors in CRS-exposed mice and modulated the imbalance of HPA axis-related hormones in mice. Mechanisms of action in the RBS were partially attributed by ORY, a key component of RBS, suggesting that ORY contributes synergistically to the effect of RBS. Thus, RBS administration could be a promising therapeutic approach to treating CRS-induced depression.