The data on the structure of conserved genes of the Old and New World orthopoxviruses and unclassified Yoka poxvirus were used for a Bayesian dating of their independent evolution. This reconstruction estimates the time when an orthopoxvirus ancestor was transferred to the North American continent as approximately 50 thousand years ago (TYA) and allows for relation of this time interval with the global climate changes (with one of the short-term warmings during the Last Ice Age). The onset of the Yoka poxvirus evolution was assessed as approximately 90TYA. Availability of a large number of genome sequences of various cowpox virus strains provided for a comprehensive analysis of the orthopoxvirus evolutionary history. Such a study is especially topical in view of the postulated role of this virus in the evolution of various orthopoxviruses, namely, as an progenitor virus. The computations have demonstrated that the orthopoxviruses diverged from the ancestor virus to form the extant species about 10TYA, while the forbear of horsepox virus separated about 3TYA. An independent evolution of taterapox, camelpox, and variola viruses commenced approximately 3.5TYA. Study of the geographic distribution areas of the hosts of these three orthopoxviruses suggests the hypothesis on the region of their origin. It is likely that these viruses first emerged in Africa, in the region of the Horn of Africa, and that the introduction of camels to East Africa induced their divergent evolution.