Non-invasive liquid biopsy is a promising strategy for ovarian cancer (OC) detection. We evaluated the feasibility and efficacy of a multi-analyte approach combining circulating tumor DNA (ctDNA) detection with protein biomarkers for early OC detection. At 95% specificity, CA125 and ctDNA alone exhibited an overall sensitivity of 79.0% and 58.7%, respectively; however, when CA125 was combined with ctDNA, sensitivity reached 85.5%. Integrating CA125 and human epididymis protein-4 (HE4) in the risk of ovarian malignancy algorithm (ROMA) index, yielded a sensitivity of 86.2%. When four additional proteins (HE4, cancer antigen 19-9, prolactin, and interleukin-6) were added to CA125 and ctDNA in the EarlySEEK model, sensitivity increased to 94.2%. Meanwhile, the EarlySEEK model was not affected by menopausal status, and outperformed CA125 in distinguishing benign and malignant ovarian tumors. These findings demonstrate that EarlySEEK could effectively identify OC at early stage when they are more likely to be curable.