Since the eradication of smallpox approximately 39 years ago, monkeypox virus remains the most pathogenic poxvirus, being mainly restricted to Central and West Africa. Before 1970, there were no reports of human monkeypox in Nigeria, while between 1971 and 1978 there were three cases, with none having been reported thereafter. However, in September 2017, a case of contagious skin rash disease, typical of monkeypox, was observed in an 11-year-old boy from the southern part of the country and confirmed to be associated with the monkeypox virus. This large outbreak consisted of 262 suspected, 115 confirmed cases, and 7 mortalities across 26 states and the Federal Capital Territory (FCT), Abuja. The aim of this manuscript is to provide an updated, comprehensive, and timely review of monkeypox, an important emerging infection in Nigeria. Monkeypox is now a major threat to global health security, requiring an urgent multidisciplinary approach involving veterinarians, physicians, virologists, and public health experts to fast-track the development of diagnostic assays, vaccines, antivirals, and other control strategies.