Background: Claudin-6 (CLDN6) is an oncofetal tight junction protein that has recently emerged as a promising therapeutic target in various solid tumors. Despite this potential, the clinical significance of CLDN6 expression in advanced-stage high-grade serous ovarian carcinoma (HGSC)—specifically its role in platinum resistance—remains poorly understood. Methods: This retrospective study analyzed 119 patients with newly diagnosed FIGO stage III–IV HGSC who received platinum-based chemotherapy at a single tertiary center between 2015 and 2025. CLDN6 expression was evaluated via immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) tumor samples. High CLDN6 expression was defined as moderate-to-strong membranous staining in ≥50% of tumor cells. Clinicopathologic associations were assessed using chi-square tests, while logistic regression analysis identified predictors of platinum resistance. Finally, overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan–Meier methods and Cox proportional hazards models. Results: High CLDN6 expression was observed in 31 patients (26%). CLDN6 expression was not significantly associated with age, CA-125 level, lymph node metastasis, distant metastasis, surgical approach, or residual disease status. However, high CLDN6 expression was significantly associated with platinum resistance (61.3% vs 28.4%, p = 0.001). In multivariable logistic regression analysis, residual disease (OR = 10.12, p> 0.001), high CLDN6 expression (OR = 4.52, p = 0.008), and elevated CA-125 levels (OR = 0.64, p = 0.041) were independently associated with platinum resistance. Median OS for the entire cohort was 43.8 months. High CLDN6 expression was associated with shorter OS (38.0 vs 45.7 months, p = 0.042) and remained an independent predictor of mortality in multivariable Cox analysis (HR = 1.90, p = 0.026). CLDN6 expression showed a trend toward shorter PFS but did not reach statistical significance (p = 0.096). Conclusions: High CLDN6 expression is associated with platinum resistance and inferior overall survival in patients with advanced-stage HGSC. These findings suggest that CLDN6 may serve as a clinically relevant biomarker for chemoresistance and tumor aggressiveness. In the context of emerging CLDN6-targeted therapies, routine assessment of CLDN6 expression may facilitate the development of biomarker-driven therapeutic strategies for advanced ovarian cancer.