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Background Platinum-based chemotherapy remains the cornerstone for treating high-grade serous ovarian cancer (HGSOC). However, its therapeutic efficacy is often compromised by the immunosuppressive tumor microenvironment (TME), and the underlying mechanisms of resistance remain unclear.Methods Tumor samples from 58 HGSOC patients were analyzed to identify immune-modulatory factors associated with cisplatin (DDP) resistance. The effects of DDP on Galectin-9 (Gal-9) expression and TME modulation were investigated using flow cytometry, immunohistochemistry, and RNA analysis. Mechanistic studies were performed to explore upstream regulatory pathways, and preclinical validation of treatment strategies was conducted in both DDP-sensitive and DDP-resistant tumor-bearing mouse models.Results Gal-9 was identified as a key immunoregulatory molecule significantly upregulated following DDP treatment. Mechanistically, DDP activated the NLRP3/Caspase-1/IL-1β axis and NF-κB pathway, resulting in Gal-9 overexpression. This induced Gal-9 contributed to an immunosuppressive TME, including increased regulatory T cells and M2-like macrophages, thereby attenuating the antitumor effects of DDP. Notably, a sequential treatment strategy—administering Gal-9 inhibition prior to DDP—effectively reversed immunosuppression, enhanced tumor regression, and significantly prolonged survival in both DDP-sensitive and -resistant murine models.Conclusions Our findings reveal that cisplatin-induced Gal-9 expression promotes immune escape and chemoresistance in HGSOC. Targeting Gal-9 prior to platinum therapy reshapes the TME, overcomes resistance, and represents a rational sequential immuno-chemotherapy approach. This strategy holds translational potential for improving outcomes in platinum-refractory ovarian cancer.