Objective: To explore the role and mechanism of 3-hydroxy-kynurenine(3-HK), a key neurotoxic metabolite in the kynurenine pathway, in bisphenol F(BPF)-induced depressive-like changes in mice and evaluate the intervention effect of leucine by intervening this pathway, thereby providing experimental evidence for identifying potential intervention targets. Methods: The BPF exposure mouse model was established to investigate its neurotoxic effects, and the depression-like behaviors were assessed through behavioral tests such as the tail-suspension test, forced swimming test, and open-field test. Concurrently, the levels of depression-related neurotransmitters, including 3-HK, 5-hydroxytryptamine(5-HT), and kynurenine were measured in the hippocampus and prefrontal cortex. Alterations in the expression levels of pro-inflammatory cytokines, including interferon-gamma(IFN-γ) and interleukin-1β(IL-1β), as well as kynurenine 3-monooxygenase(KMO), were also detected. Furthermore, a leucine combined intervention group was established to assess whether BPF-induced depression-like behaviors improved, with additional measurements of neurotransmitter levels, pro-inflammatory factors, and KMO expression. The role of 3-HK in BPF-induced reactive oxygen species(ROS) generation in primary neurons was investigated using a fluorescent probe assay. Results: BPF exposure induced depressive-like behaviors in mice. While 5-HT levels in the hippocampus and cortex showed no significant change, the content of kynurenine was markedly reduced. BPF exposure significantly increased the expression levels of KMO in the hippocampus and cortex, and promoted the accumulation of 3-HK, which facilitated the production of pro-inflammatory factors such as IFN-γ and IL-1β by activating the inflammatory pathway. Leucine intervention alleviated BPF-induced depressive-like behavior, significantly reversing the abnormal expression of KMO and pro-inflammatory factors, and notably reducing 3-HK levels, though other neurotransmitter levels remained largely unchanged. Meanwhile, competitive inhibition of 3-HK transport or inhibition of KMO significantly reversed the ROS caused by BPF. Conclusion: BPF exposure upregulates KMO expression in the hippocampus and cortex, leading to abnormal accumulation of 3-HK, which subsequently triggers excessive ROS generation and neuroinflammation. These pathological changes may collectively contribute to neural damage and depression-like behaviors. In contrast, leucine inhibits this metabolic shift, alleviates oxidative stress and inflammation, thereby mitigating depression-like behaviors.