Studies have shown that morbidity of several diseases varies between males and females. This difference likely arises due to sex-related hormones. Estrogen, a primary female sex steroid hormone, plays a critical role in mediating many of the physiological functions like growth, differentiation, metabolism, and cell death. Recently, it has been demonstrated that estrogen mediates autophagy through its receptors (ERs) namely ERα, ERβ, and G-protein coupled estrogen receptor (GPER). However, the specific role of estrogen and its receptors mediated-autophagy in cell fate and human diseases such as cancers, cardiovascular disease and nervous system disease remains unclear. In this review, we comprehensively summarize the complex role of estrogen and its receptors-mediated autophagy in different cell lines and human diseases. In addition, we further discuss the key signaling molecules governing the role of ERs in autophagy. This review will serve as the basis for a proposed model of autophagy constituting a new frontier in estrogen-related human diseases. Here, we discuss the dual role of ERα in classical and non-classical autophagy through B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). Next, we review the role of ERβ in pro-survival pathways through the promotion of autophagy under stress conditions. We further discuss activation of GPER via estrogen often mediates autophagy or mitophagy suppression, respectively. In summary, we believe that understanding the relationship between estrogen and its receptors mediated-autophagy on cell fate and human diseases will provide insightful knowledge for future therapeutic implications.