Background: Exosomes, harboring donor-cell-derived biomarkers, are implicated in transferring oncologic protein and genetic materials. CD200, an immune checkpoint, has been engineered to affect immunosuppression in ovarian cancer. However, the potential of CD200 to serve as a predictor of ovarian cancers remains unexplored. Methods: We performed dynamic measurements of exosome-mediated or serum CD200 levels at primary diagnosis, post-operation, and three cycles after chemotherapy. The receiver operating characteristic curve and cumulative survival rate were paralleled to decode the predictive and prognostic profiles. Results: Independent enrichment and identification of exosomes revealed a significant concentration of CD200, predominantly located within these exosomes. The CD200 level was elevated in non-responders compared to responders at the serial points and significantly decreased after treatment. At the 335.50 pg/mL cut-off, CD200 at primary diagnosis enabled accurate discrimination between responders and non-responders with an area under the curve (AUC) of 0.94 (95% confidence interval (CI) = 0.902–0.979, p = 0.01). With the cut-off dropping from 311.00 pg/mL to 265.00 pg/mL, the AUC decreased from 0.918 (95% CI = 0.873–0.963, p = 0.02) to 0.908 (95% CI = 0.862–0.955, p = 0.02), respectively. Elevated levels of CD200 levels at both primary diagnosis and three cycles after chemotherapy were identified as independent predictors for poor progression-free survival (PFS) (hazard ratio (HR) = 2.8, 95% CI = 2.08–3.49, p = 0.01; HR = 6.7, 95% CI = 4.01–8.02, p = 0.01, respectively) and overall survival (OS) (HR = 3.5, 95% CI = 2.14–4.99, p = 0.04; HR = 5.6, 95% CI = 3.01–7.34, p = 0.01, respectively). Based on CD200 dynamics, patients were stratified into high- and low-AUC groups. High CD200-AUC was independently associated with unfavourable PFS and OS (HR = 4.6, 95% CI = 3.6–15.7, p = 0.01; HR = 3.2, 95% CI = 1.5–6.3, p = 0.01, respectively). Conclusions: This study proposes high exosome-mediated CD200 as a liquid-based biomarker indicative of chemotolerance and dismal survival in ovarian neoplasms.