Objectives The early groups of hunter‐gatherers who peopled South America faced significant ecological changes in their trophic niche for a relatively short period after the initial peopling. In particular, the incorporation of cultigens during the Holocene led to a wider trophic niche and probably to an increased carrying capacity of the environment. Here, we study the relationship between the incorporation of domestic resources during the Holocene and the demographic dynamics of human populations at a regional scale in South America. Material and methods We employ mitochondrial DNA (mtDNA), radiocarbon data and Bayesian methods to estimate differences in population size, human occupation and explore the demographic changes of human populations in three regions (i.e., South‐Central Andes, Northwest, and South Patagonia). We also use archaeological evidence to infer the main diet changes in these regions. Results The absolute population size during the later Late Holocene was fifteen times larger in the South‐Central Andes than in Northwest Patagonia, and two times larger in the latter region than in South Patagonia. The South‐Central Andes display the earlier and more abrupt population growth, beginning about 9000 years BP, whereas Northwest Patagonia exhibits a more slow growth, beginning about 7000–7500 years BP. South Patagonia represents a later and slower population increase. Discussion In this work we uncovered a well‐supported pattern of the demographic change in the populations from South‐Central Andes and Patagonia, obtained on the basis of different data and quantitative approaches, which suggests that the incorporation of domestic resources was paramount for the demographic expansion of these populations during the Holocene.