This article aims to investigate about the social stigma and the prejudice of society towards the patients with leprosy, but also to understand how this infectious disease has largely influenced human lifestyle and evolution analyzing the evolution of its treatments from past empirical treatments to actual multidrug therapy (MDT). References on leprosy were extensively searched in literature using PubMed, Web of Science, Medline, Springer link and Elsevier’s (EMBASE.com) databases, but also in medical, religious and archaeological books. Leprosy’s spread all around the world following human paths of migration from the African Continent to the Asian one and to Europe, instead its appearance in the New Continent is more recent. Wars, unhygienic conditions, social and health inequality created conditions for its spread since prehistorical times, and existing health disparities contributed to unequal morbidity and mortality, before its gradual decline after the Middle Ages due to the raise of other worse pandemics. Starting from Renaissance, a deeper knowledge on its pathophysiological mechanisms brought an increasingly advanced combined surgical and pharmacological treatment, but still in modern times many efforts have been made to erase its social stigma, changing its name in “Hansen’s disease” included.