BackgroundMajor depressive disorder is prevalent across different societies, affecting individuals from various cultural and socioeconomic backgrounds. Dysregulation of the nitric oxide (NO) pathway and increased oxidative stress have been implicated as contributing factors. PurposeThis study aimed to explore the antidepressant potential of β-caryophyllene in a mouse model subjected to maternal separation stress, with a focus on its effects on oxidative stress and nitrite levels. Study DesignThe research involved 40 male mice, which were divided into five groups. MethodsThe control group received 1 ml/kg of normal saline, while the maternal separation (MS) groups were administered normal saline in conjunction with β-caryophyllene at doses of 10, 20, and 50 mg/kg. Various behavioral tests, including the open field test (OFT), forced swimming test (FST), and splash test, were employed to assess the impact of β-caryophyllene. Additionally, measurements of total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels in the hippocampus were conducted. ResultsThe findings demonstrated that maternal separation stress induced depressive-like behaviors in mice, as evidenced by increased immobility time in the FST and decreased grooming behavior in the splash test. Furthermore, MS was associated with elevated MDA and nitrite levels and reduced TAC in the hippocampus. However, administration of β-caryophyllene increased grooming activity in the splash test and decreased immobility time in the FST. Additionally, β-caryophyllene exhibited antioxidant properties, lowering MDA and nitrite levels while enhancing TAC in the hippocampus. ConclusionThese results suggest that β-caryophyllene may possess antidepressant-like effects in mice subjected to maternal separation, likely due to its antioxidant actions in the hippocampus.