Various factors interfere with the endoplasmic reticulum (ER) function, which is involved in protein folding and calcium homeostasis. ER dysfunction referred to as ER stress triggers cell death by apoptosis and inflammation. Berberine (BBR) is an alkaloid extracted from the family Berberidacea. It has shown multiple pharmacological activities, including anti-inflammatory, antioxidative, anti-apoptotic, antiproliferative, and antihypertensive. It has been reported that BBR can decrease apoptosis and inflammation following different pathological conditions, which might be mediated by targeting ER stress pathways. In this manuscript, we reviewed the protective potential of BBR against several diseases, such as metabolic disorders, cancer, intestinal diseases, cardiovascular, liver, kidney, and central nervous system diseases, in both in vivo and in vitro studies.