Background Ovarian-Adnexal Reporting and Data System (O-RADS) US provides a standardized method with which to stratify lesions into risk of malignancy categories, which is crucial for proper management. Purpose To perform a systematic review and meta-analysis to estimate malignancy rates for each O-RADS US score and evaluate the diagnostic performance of combined O-RADS US scores 4 and 5 in the diagnosis of malignancy. Materials and Methods A systematic literature search from the inception of the MEDLINE, EMBASE, and Web of Science databases through January 27, 2023, was performed for articles that reported using the O-RADS US stratification system and included malignancy rates per each O-RADS score. Bivariate random-effects models were used to determine the pooled malignancy rates for each O-RADS US score and to obtain summary estimates of the diagnostic performance of combined O-RADS US scores 4 and 5 in the diagnosis of malignant lesions. Results The final analysis included 18 studies consisting of 11 605 patients and 11 818 ovarian-adnexal lesions, with 2996 malignant (25.4%) and 8822 benign (74.6%) lesions. No malignant lesions were reported in O-RADS 1 category. The pooled percentages of malignancy were 0.6% (95% CI: 0.3, 1.0) for O-RADS 2, 3.9% (95% CI: 2.5, 5.4) for O-RADS 3, 43.5% (95% CI: 33.8, 53.2) for O-RADS 4, and 87.3% (95% CI: 83.0, 91.7) for O-RADS 5. The pooled sensitivity and specificity of combined O-RADS scores 4 and 5 in the diagnosis of malignant lesions were 95.6% (95% CI: 94.0, 97.2) and 76.6% (95% CI: 70.4, 82.7), respectively. Conclusion Each O-RADS US score provided the intended probability of malignant lesions as outlined by the O-RADS risk stratification system. When O-RADS US scores 4 and 5 were combined as a predictor for malignancy, O-RADS US showed a high sensitivity and moderate specificity. Clinical trial registration no. CRD42022352166 © RSNA, 2023 Supplemental material is available for this article.