Human paleodemographic changes were related to environmental fluctuations for the North American Arctic and boreal region, including Greenland. Using the frequency of archaeological radiocarbon dates as a proxy for population size, past changes in population were estimated and quantitatively examined in relation to reconstructions of temperature and sea ice conditions. This analysis was conducted across three spatial scales in order to better identify potential climate impacts on population size: the entire area, four major cultural-environmental regions and sixteen sub-regions. The timing of initial settlement differed by region, and population size fluctuated through time, but there was nevertheless an overall, accelerating increase in most areas. There was a high correspondence between millennial and centennial-scale climate variability and paleodemographic changes across the region, with population size generally increasing during warmer periods and decreasing during cooling episodes. Late Holocene cooling (neoglaciation) triggered a nearly-synchronous population decline across the entire region at 3.9 ka, a time when significant societal disruptions have been identified around the world, and are here shown in the Arctic. Decreasing temperatures and increased sea ice coverage also influenced large-scale migration patterns of Paleo-Inuit peoples as well as their cultural evolution. The growth of Paleo-Inuit populations after 3 ka during continued climate cooling is consistent with archaeological evidence suggesting Paleo-Inuit technological change enabled adaptations to increased sea ice. •Multi-scale analysis of human-environment interactions discerns local and regional population dynamics.•Climate changes caused increases and decreases in population in the Arctic and Subarctic.•Neoglaciation triggered continental-scale population decline across the north.•Population density underwent long-term growth despite climate-induced regional decreases.