AbstractMonkeypox (MPX) is a common zoonotic disease caused by a double-strand DNA MPX virus (MPXV). MPX was considered a sporadic rare disease causing a mild disease with a low capacity to spread among humans. The clinical picture of human MPX highly resembles smallpox, though early lymphadenopathy in human MPX is the distinguishing sign not present in smallpox. The incubation period is 1–3 weeks, and fever, headache, joint pain, myalgia, and nausea for about 3 days. Skin lesions that appear 1–3 days following fever and lymphadenopathy usually appear simultaneously on the face and periphery. By cross-reactivity and protection, the smallpox vaccine produced 85% protection against infection with Orthopoxviruses, including MPX. Antiviral drugs like tecovirimate and brincidofovir could be effective agents against the development of MPX. MPX epidemics are less reported and described as other life-threatening epidemics, leading to an unclear picture of this disease’s pathogenesis, epidemiology, and management. With the recent wide range of MPX outbreaks, immense research is mandatory to revise the importance of MPX pathogenesis and risk for epidemic development worldwide. Therefore, this critical study aimed to review MPX's pathogenesis, epidemiology, and management with possible repurposed drugs.