Background: The diagnosis of advanced endometriosis remains challenging with considerable limitations in the diagnosis of retroperitoneal and deep infiltrating lesions. Thus, a well-defined panel of inexpensive, noninvasive inflammatory biomarkers could be a crucial tool for appropriate staging for women with suspected endometriosis. The aim of this work is to explore the potential use of serum YKL-40, interleukin-37 (IL-37), and cancer antigen 125 (CA125) for noninvasive staging of endometriosis patients for proper intervention and most optimal management of the condition. Methods: This study was conducted on 90 women, who had undergone laparoscopic or laparotomy surgery due to suspected pelvic endometriosis. Blood samples for serum YKL-40, IL-37, and CA125 levels assay were taken from all participants at admission for laparoscopy or laparotomy. After histopathological confirmation of the diagnosis, the selected cases were immunostained for YKL-40, IL-37, and CA125. Results: YKL-40, IL-37, and CA125 serum levels were significantly elevated in patients with endometriosis than healthy controls. Moreover, the association between the serum level and immunoexpression and grading of endometriosis. A triple combination panel of serum YKL-40, IL-37, and CA125 was found to have the best sensitivity and specificity (96.67% and 100.0%, respectively) compared to any single serum marker alone or double combination panel in predicting the severity of endometriosis. Conclusions: A triple combination panel of serum YKL-40, IL-37, and CA125 could be used in the future for predicting endometriosis stage, providing a practical reference for making better-informed decisions on the best treatment plan