As a variant of Vaccinia virus, Buffalopox virus is known to cause Buffalopox disease. In recent times, sporadic outbreaks of the infection in humans have been reported, especially in the endemic countries of Southeast Asia. Though mortality has not been high, associated morbidity is significant. Due to waning cross-protective immunity against smallpox, Buffalopox virus is one of the several orthopox viruses likely to emerge or reemerge. To combat this virus, early recognition, isolation, and management of the infection in animals and humans is of prime importance. In addition, vaccination in animals and humans at risk of acquiring infection is essential as a means of limiting animal-to-animal and animal-to-human spread of the virus. With this in mind, a collaborative approach between the animal and human health sectors is indispensable.