Objective: To investigate the diagnostic value of interleukin-37 (IL-37), combined with carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) in epithelial ovarian cancer (EOC). Methods: Seventy-six patients with EOC (EOC group) and 80 patients with benign ovarian tumor (benign group) pathologically diagnosed after surgery in our hospital from January 2018 to December 2020 were selected. The serum levels of IL-37, CA125 and HE4 were detected. The differences of each index level were compared between each group, and the receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic efficacy of each index and its combination for EOC. Results: The levels of IL-37, CA125 and HE4 in the EOC group were higher than those in the benign group (P<0.05). The level of IL-37 was correlated with tumor size, FIGO stage and lymph node metastasis (P<0.05), but not related to age and menopausal status (P>0.05). ROC curve analysis showed that the area under the curve of IL-37 diagnosing EOC was 0.737 (95%CI: 0.659–0.805), the area under curve of CA125 was 0.857 (95%CI: 0.791–0.909), and the area under curve of HE was 0.746 (95%CI: 0.642–0.808), and the area under curve of the combination of the three was 0.932 (95%CI: 0.879–0.966), which was higher than the single index, and the difference was statistically significant (P<0.05). The area under the curve of the three combined diagnosis of early EOC was 0.952 (95%CI: 0.706–0.893), which was also higher than that of single IL-37 [0.867 (95%CI: 0.769–0.934)], CA125 [0.822 (95%CI: 0.717–0.900)], HE4 [0.812 (95%CI: 0.706–0.893)], the difference was statistically significant (P<0.05). Conclusion: Serum IL-37 is associated with tumor size, clinical stage and lymph node metastasis of EOC, and has certain diagnostic value for EOC, combination of CA125 and HE4 can improve the specificity of diagnosis.