Perimenopausal depression is a subtype of depression that seriously harms women's health. The pathogenesis of perimenopausal depression remains unclear, which limits its prevention and therapy. Quercetin is a flavonoid with antidepressant and estrogen-like effects. This study aimed to explore the effects of quercetin on spleen metabolism in rats with perimenopausal depression and its potential mechanism. Untargeted metabolomics was employed to obtain splenic metabolite profiles, and 21 differential metabolites were identified. Pathway analysis revealed that glycerophospholipid metabolism, retinol metabolism, steroid hormone biosynthesis, and linoleic acid metabolism were disturbed. Notably, Spearman's rank correlation analysis revealed that differential metabolites were significantly correlated with behavioral test results (p <
0.01). After treatment with quercetin, the intensities of the above differential metabolites were restored (p <
0.01), indicating that quercetin can improve the spleen metabolic disorder induced by the perimenopausal depression model. Further study showed that quercetin can increase the expression of PPAR-α in the hippocampus and spleen, reduce the expression of NF-κB and the levels of TNF-α and IL-6 in the spleen, and restore the expression of CREB and BDNF in the hippocampus (p <
0.05 or p <
0.01). Our study is the first to explore the effect of quercetin on spleen metabolism disorders in perimenopausal depression model rats using untargeted metabolomics. Quercetin can improve spleen metabolism disorders through multiple pathways, which may be related to the restoration of hippocampal neuroplasticity and reduction of spleen inflammation by regulating the brain-spleen axis. Our study provides a potential strategy for preventing and treating perimenopausal depression.