Background: Endometriosis is a benign gynaecological disease with malignant characteristics that severely affects women's quality of life. Long noncoding RNA maternally expressed gene 3 (LncRNA MEG3) is a tumour suppressor that is downregulated in various cancer cells and tissues, and regulates multiple biological processes. Emerging studies have revealed that the interactions between MEG3 and proteins are involved in disease progression. Galectin-1 affects cell motility, signal transduction and vascularization, and is overexpressed in endometriosis. Our study is the first to explore the role of MEG3-210 transcript in endometriosis and to reveal the regulatory mechanism mediated by the interaction between MEG3-210 and Galectin-1. Materials and methods: Endometrial tissues and sera from patients with endometriosis and controls were collected. qRT-PCR was performed to detect the expression of MEG3-210 in the endometrium and endometrial stromal cells (ESCs). The CCK-8 assay, the Transwell assay, flow cytometry and animal models were conducted to evaluate the functions of MEG3-210 in vitro and in vivo. Bioinformatic analysis, Western blot assays, RNA-pull down assays and RNA immunoprecipitation were used to explore the potential mechanism of MEG3-210 in endometriosis. Results: Our results showed that MEG3-210 expression was lower in the eutopic endometrium of women with endometriosis. MEG3-210 downregulation promoted ESCs migration, invasion, anti-apoptosis in vitro and growth of endometriotic lesions in vivo. Furthermore, MEG3-210 downregulation could activate p38 mitogen-activated protein kinase (p38 MAPK) and inhibit cAMP-dependent protein kinase A/sarcoplasmic reticulum Ca2+ ATPase 2 (PKA/SERCA2) signalling, which was mediated by Galectin-1. The protein levels of Galectin-1 in patients with endometriosis were elevated, and Galectin-1 siRNA could reduce the size of lesions. Conclusion: MEG3-210 regulates ESCs through p38 MAPK and PKA/SERCA signalling via interaction with Galectin-1. The novel regulatory mechanism may provide new insights into drug therapy and the diagnosis of endometriosis.Keywords: Endometriosis; Galectin-1; SERCA2; lncRNA; p38 MAPK.