Endometriosis has been shown to increase the risk of gynecological cancers. However, the effect of gestrinone, a clinical endometriosis drug, on gynecological cancers remains unclear. This study aimed to understand the effect of gestrinone on gynecological cancers. A retrospective study was conducted using the Longitudinal Health Insurance Database 2000 of the Taiwan National Health Insurance Research Database (NHIRD) to observe the risk of gynecological cancers. Medication records from the Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital CSMUH and cancer records from the Taiwan Cancer Registry were collected to analyze the correlation between gestrinone use and gynecological cancers. Subsequently, human cell lines were used to investigate the effect of gestrinone on gynecological cancers. A total of 8330 endometriosis patients were enrolled, and analyses revealed that endometriosis patients had a higher risk of developing ovarian and endometrial cancer. However, the rate of cervical cancer was not statistically different (P = 0.249). Analyses of both the NHIRD and CSMUH databases revealed that gestrinone may reduce the risk of gynecological cancer. Cellular experiments verified the anticancer effects of gestrinone, which effectively and specifically inhibited the growth of HeLa cervical cancer cells, decreased P21 expression via JNK phosphorylation, and induced apoptosis. Combining the results of clinical database analysis and cell experiments, our findings prove that gestrinone has the potential to protect against cancer through regulation of the JNK-P21 axis. Repurposing the anticancer efficacy of gestrinone may be a strategy for targeted therapy in the future.