AIMS: The present study aimed to examine the roles of circRNA-circSMAD2 and its regulatory mechanisms in endometriosis (EMs). BACKGROUND: Evidence has confirmed that circRNAs play multiple roles in regulating the occurrence and development of EMs, but the regulatory mechanisms of circRNAs in EMs remain largely unknown. OBJECTIVE: The roles and regulatory mechanisms of circSMAD2 in EMs. METHOD: Eutopic and ectopic endometrium of ovarian EMs as well as normal endometrial tissues, were used to extract circRNA, mRNA, and total proteins. The human endometrial stromal cell lines (ThESCs) and endometrial stromal cells (ESCs) were stimulated with different concentrations or times of 17β-estradiol (E2). The mouse model of EMs was established by implanting uterine horns onto the peritoneum wall using a suture. RESULT: Compared with normal tissues, the expression of circSMAD2 was significantly decreased in eutopic and ectopic endometrial tissues. Furthermore, the expression of circSMAD2 was downregulated by E2 in a dose- and time-dependent manner in ThESCs and ESCs. Overexpression of circSMAD2 inhibited the invasion and migration of ThESCs, while knockdown of circSMAD2 exerted the opposite effect. The RNA binding protein quaking (QKI), which is involved in circRNA formation, was lower in eutopic and ectopic endometrial tissues compared to normal tissues. CONCLUSION: Moreover, E2 suppressed the expression of circSMAD2 by inhibiting the expression of QKI. Additionally, E2 enabled the expression of estrogen receptor beta (ERβ) to inhibit the expression of QKI and circSMAD2 in vitro and in vivo. CONCLUSION: The E2/ERβ/QKI/circSMAD2 pathway was involved in cellular migration and invasion in EMs.