Breast cancer is the most prevalent malignancy that affects women worldwide, with approximately 70% of cases classified as hormone receptor-positive (HR+). Endocrine therapy is one of the principal treatment modalities for this patient cohort. However, a considerable proportion of tumors acquire resistance to endocrine therapeutics, resulting in reduced effectiveness as the disease progresses, but the underlying mechanisms are not fully characterized. The G protein-coupled estrogen receptor (GPER), a component of the G protein-coupled receptor family, is hypothesized to mediate estrogenic effects independently of conventional estrogen receptors. In recent years, our research group and others have demonstrated that GPER plays a crucial role in facilitating the clinical progression of HR+ breast cancer and significantly contributes to endocrine resistance. In this review, we summarize the diverse mechanisms through which GPER mediates endocrine resistance, encompassing somatic alterations, epigenetic and non-genetic variations, and modifications within the tumor microenvironment. Furthermore, we discuss GPER as a potential therapeutic target for overcoming endocrine resistance of HR+ breast cancer in future clinical applications.