The onset of plant cultivation is one of the most important cultural transitions in human history1–4. Southwestern Amazonia has previously been proposed as an early centre of plant domestication, on the basis of molecular markers that show genetic similarities between domesticated plants and wild relatives4–6. However, the nature of the early human occupation of southwestern Amazonia, and the history of plant cultivation in this region, are poorly understood. Here we document the cultivation of squash (Cucurbita sp.) at about 10,250 calibrated years before present (cal. yr bp), manioc (Manihot sp.) at about 10,350 cal. yr bp and maize (Zea mays) at about 6,850 cal. yr bp, in the Llanos de Moxos (Bolivia). We show that, starting at around 10,850 cal. yr bp, inhabitants of this region began to create a landscape that ultimately comprised approximately 4,700 artificial forest islands within a treeless, seasonally flooded savannah. Our results confirm that the Llanos de Moxos is a hotspot for early plant cultivation and demonstrate that—ever since their arrival in Amazonia—humans have markedly altered the landscape, with lasting repercussions for habitat heterogeneity and species conservation.