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There are more than 30 species of Glycyrrhiza genus extensively spread worldwide. It was the most prescribed herb in Ancient Egyptian, Roman, Greek, East China, and the West from the Former Han era. There are various beneficial effects of licorice root extracts, such as treating throat infections, tuberculosis, respiratory, liver diseases, antibacterial, anti-inflammatory, and immunodeficiency. On the other hand, traditional medicines are getting the attraction to treat many diseases. Therefore, it is vital to screen the medicinal plants to find the potential of new compounds to treat chronic diseases such as respiratory, cardiovascular, anticancer, hepatoprotective, etc. This work comprehensively reviews ethnopharmacological uses, phytochemistry, biological activities, clinical evidence, and the toxicology of licorice, which will serve as a resource for future clinical and fundamental studies. An attempt has been made to establish the pharmacological effect of licorice in different diseases. In addition, the focus of this review article is on the molecular mechanism of licorice extracts and their four flavonoids (isoliquiritigenin, liquiritigenin, lichalocone, and glabridin) pharmacologic activities. Licorice could be a natural alternative for current therapy to exterminate new emerging disorders with mild side effects. This review will provide systematic insights into this ancient drug for further development and clinical use.