Archaeological evidence indicates that the original settlement of the Altai occurred by ∼800 ka. The next major wave of hominin migration occurred by approximately 500–400 ka, followed by another one at ∼300 ka. Archaeological findings indicate a continuous evolution of lithic industries between 80 and 10 ka across the Altai. At about 55–45 ka, a small group of Neanderthals appeared in the Altai, producing various forms of lithics at places such as Okladnikov Cave and Chagyrskaya Cave. In the case of Denisova Cave, we suggest that the probable assimilation of Neanderthals occurred without any significant changes in material culture. The current archaeological patterns are well matched with the paleogenomic data from the region. Genetic data suggest that Denisovans were present in the area during at least two separate occasions and over a long period of time, with their presence perhaps interrupted by Neanderthal occupation. The analysis of odontological data shows that Denisovans preserved some archaic morphological features. The archaeological data, along with fragmentary human remains, demonstrate significantly different patterns in comparison with contemporary sites in eastern Asia. The specific position of the Denisovans could possibly be explained as a result of the temporal and geographic isolation of the migrant groups over a long period of time, with the ancestral population originating from western Asia.