Objective Serous ovarian carcinoma (OC) represents a leading cause of cancer-related death among U.S. women. Non-invasive tools have recently emerged for discriminating benign from malignant ovarian masses, but evaluation remains ongoing, without widespread implementation. In the last decade, metabolomics has matured into a new avenue for cancer biomarker development. Here, we sought to identify novel plasma metabolite biomarkers to distinguish serous ovarian carcinoma and benign serous ovarian tumor. Methods Using liquid chromatography-mass spectrometry, we conducted global and targeted metabolite profiling of plasma isolated at the time of surgery from 50 serous OC cases and 50 serous benign controls. Results Global lipidomics analysis identified 34 metabolites (of 372 assessed) differing significantly (P < 0.05) between cases and controls in both training and testing sets, with 17 candidates satisfying FDR q < 0.05, and two reaching Bonferroni significance. Targeted profiling of ~ 150 aqueous metabolites identified a single amino acid, alanine, as differentially abundant (P < 0.05). A multivariate classification model built using the top four lipid metabolites achieved an estimated AUC of 0.85 (SD = 0.07) based on Monte Carlo cross validation. Evaluation of a hybrid model incorporating both CA125 and lipid metabolites was suggestive of increased classification accuracy (AUC = 0.91, SD = 0.05) relative to CA125 alone (AUC = 0.87, SD = 0.07), particularly at high fixed levels of sensitivity, without reaching significance. Conclusions Our results provide insight into metabolic changes potentially correlated with the presence of serous OC versus benign ovarian tumor and suggest that plasma metabolites may help differentiate these two conditions.