This review sheds light on the protective effect of estrogen and its receptors especially GPER activation on several diseases in previous studies. Activating estrogen receptors in different organs causes protection against kidney, liver, cardiovascular, and neurological diseases in addition to their protective role on metabolic disorders as insulin resistance. Estrogens are a class of female hormones, including estrone, estradiol, estriol, and estetrol. Estradiol is the most common circulating estrogen in humans, secreted by ovarian follicles and corpus lutea. Recent and previous studies have shown that estrogens are important regulators of many brain functions. It can also prevent hepatocellular carcinoma (HCC) from developing. Additionally, it is widely known that endogenous estrogen has a crucial role in lowering the incidence of cardiovascular disorders in women due to its antioxidant ability. Furthermore, estrogens have a direct pro-apoptotic effect on osteoclasts, which makes premenopausal women more protected than men from osteoporosis and bone disease. Estrogen also protects women from metabolic disorders as with the onset of menopause, metabolic abnormalities such as insulin resistance tend to increase markedly. Two different structural receptor classes, namely G protein-coupled estrogen receptor (GPER) and estrogen receptor (ER) α/β, mediate the effects of estrogen in both normal and pathological circumstances.