The Holocene, encompassing the last 11,700 years, stands out as a truly unique epoch, marking the most recent chapter in mammalian history. In South America, a region characterized by vast territory and remarkable environmental diversity, understanding of geobiotic evolution over the past 11,700 years remains limited. While considerable attention has been given to the Great American Biotic Interchange, Pleistocene mammals and, particularly, to megamammals and their extinction, much less is known about Holocene mammal assemblages. In most of the published analyses, Holocene communities are considered a kind of residuum after the megamammal extinction, without major ecological significance. Typically, data on Holocene mammal assemblages derives from archaeological sites and is often linked to human settlement in South America. This inherent bias constrains interpretations, leading to a fragmented mosaic of selected mammalian resources, rather than a comprehensive view of the entire assemblage. This chapter aims to provide an elementary discussion on South America’s mammalian evolution during the Holocene. Several fossil records (archaeological and paleontological) were reviewed from the last 11,700 years in Argentina, Brazil, and Chile, and, based on these records, taphonomic, paleoecological, and biogeographical aspects are addressed. Mega-, large-, and medium-sized mammals predominantly entered the areas where the sites are through human hunting, carnivore predation, and natural attritional processes. In contrast, small mammals (mainly rodents, marsupials, and bats) were primarily deposited through the predatory activities of birds of prey. Postglacial mammal communities exhibited taxonomic stability or only minor variations until the late Holocene and historical periods, when certain specialized taxa experienced biological extinctions and regional extirpations. However, contrastingly, several taxa, including both small and large mammals, suffered important expansions and contractions in their geographic ranges. During the late Holocene-Anthropocene transition, 11 mammalian species were extirpated on the South American mainland. Multiple factors, including overexploitation and habitat loss, have been proposed to explain these declines. Human influence and climate change also appear to play significant roles in shaping current mammal assemblages during the Anthropocene, as evidenced by the Patagonian case study briefly addressed here.