The broader territory of the Urals has principal significance for elucidating the historical processes and environmental contexts of the Pleistocene expansion of people from the south-eastern parts of Europe into West Siberia and the northern Russian Arctic regions. Interaction of past climate change and the regional topographic modelling triggered by neotectonic activity reflected by pronounced natural transformations attest to the complexity of the Quaternary development in the Central Urals, affecting timing and intensity of the earliest human occupation of this territory. The initial peopling of the western (Fore-Ural) area is associated with the Early Palaeolithic dispersal into the marginal East European Plain, probably during some climatically favourable Middle Pleistocene interglacials. The Chusoaya River valley transecting the Central Ural Mountain range was one of the main geographic corridors for the subsequent Middle and Upper Palaeolithic migrations into the eastern (Trans-Ural) regions of West Siberia. A long-term behavioural adjustment to cold periglacial habitats is linked to progressive cultural and biological evolution during the Late Pleistocene. The north-central Trans-Urals Upper Palaeolithic Complex in the Sosva River basin with open occupation sites based on “mammoth fauna” exploitation indicates adaptation to sub-polar tundra-steppe environments of the West Siberian Plain during the last glacial stage. Geoarchaeological records provide further insights into the timing and ecology conditions of the Pleistocene colonisation of north-central Eurasia. The present study summarises the current evidence on trajectories of the Pleistocene environmental development in the broader Central Urals, still a marginally investigated geographical area of Eurasia.