Background: Breast cancer-related depression (BCRD) is strongly associated with BC and increases recurrence and mortality. This study investigated the role of kaempferol in the pathogenesis of BCRD and its underlying mechanism. Methods: 4T1 mouse BC cells were treated with corticosterone (Cort) in vitro to develop a neuronal injury model, and a BCRD mouse model was established by injecting 4T1 cells and Cort. The effects of kaempferol on 4T1 cells and BCRD models were measured by behavioral tests, Cell Counting Kit-8 assay, wound healing assay, colony formation assay, Western blot analysis, quantitative real-time PCR, hematoxylin and eosin staining, enzyme-linked immunosorbent assay, and immunofluorescence. BCRD cells were transfected with the cyclo-oxygenase-2 (COX-2) overexpression plasmid to study the role of the COX-2/prostaglandin E2 (PGE2) axis in the anti-BCRD activity of kaempferol. The connection between kaempferol and COX-2 was analyzed by molecular docking. Results: Kaempferol reduced the viability, migration, and clones of 4T1 cells and inhibited BC growth and depression-like behavior in mice. Kaempferol alleviated inflammation in BCRD, decreased interleukin 1 beta (IL-1\beta) and IL-6 levels, and increased transforming growth factor beta 1 (TGF-\beta1) and IL-10 levels. In addition, kaempferol elevated the levels of serotonin, dopamine, and norepinephrine and the amount of 5-Bromo-2{}^{\prime }-deoxyuridine/neuronal nuclei-positive cells. Kaempferol downregulated COX-2 and PGE2, and kaempferol could dock with the protein structure of COX-2. Overexpression of COX-2 reduced BCRD viability, upregulated IL-1\beta and IL-6 levels, and downregulated TGF-\beta1 and IL-10 expression. Overexpression of COX-2 reversed the protective effects of kaempferol. Conclusion: Kaempferol exerted anti-BCRD effects, at least in part by inhibiting the COX-2/PGE2 pathway, which regulates neuroinflammation, neurotransmitter imbalance, and defective neurogenesis. Therefore, kaempferol may be a promising candidate active ingredient for treating BCRD.