According to previous literatures, plasma thioredoxin reductase (TrxR) level was significantly elevated in various malignant tumors and serve as a potential biomarker for diagnosis and prognostic prediction. However, there is little awareness of the clinical value of plasma TrxR in gynecologic malignancies. In the present study, we aim to evaluate the diagnostic accuracy of plasma TrxR in gynecologic cancer and explore its role in treatment surveillance. We retrospectively enrolled 134 patients with gynecologic cancer and 79 patients with benign gynecologic disease. The difference of plasma TrxR activity and tumor markers level between two groups was compared using Mann-Whitney U test. By detecting pretreatment and post-treatment level of TrxR and conventional tumor markers, we further assessed the change trend of them with the Wilcoxon signed-ranks test. Compared with benign control [5.7 (5, 6.6) U/mL], statistically significant increase of TrxR activity was observed in gynecologic cancer group [8.4 (7.25, 9.825) U/mL] (P < .0001), regardless of age and stage. On the basis of receiver operating characteristic (ROC) curves, we found plasma TrxR shows the highest diagnostic efficacy for distinguishing malignancy with benign disease, with an area under the curve (AUC) of 0.823 (95% confidence interval [CI] = 0.767-0.878), in the whole cohort. Besides, patients receiving treatment previously [8 (6.5, 9) U/mL] had a decreased TrxR level relative to treatment-native patients [9.9 (8.6, 10.85) U/mL]. Furthermore, follow-up data showed that plasma TrxR level would be evidently decreased after two courses of antitumor therapy (P < .0001), which is consistent with the downward trend of conventional tumor markers. Collectively, all these results demonstrated plasma TrxR is an effective parameter for gynecologic cancer diagnosis and concurrently acts as a promising biomarker for treatment response assessment.