The Neolithic Revolution narrative associates early-mid Holocene domestications with the development of agriculture that fueled the rise of late Holocene civilizations. This narrative continues to be influential, even though it has been deconstructed by archaeologists and geneticists in its homeland. To further disentangle domestication from reliance on food production systems, such as agriculture, we revisit definitions of domestication and food production systems, review the late Pleistocene–early Holocene archaeobotanical record, and quantify the use, management and domestication of Neotropical plants to provide insights about the past. Neotropical plant domestication relies on common human behaviors (selection, accumulation and caring) within agroecological systems that focus on individual plants, rather than populations—as is typical of agriculture. The early archaeobotanical record includes numerous perennial and annual species, many of which later became domesticated. Some of this evidence identifies dispersal with probable cultivation, suggesting incipient domestication by 10,000 years ago. Since the Pleistocene, more than 6500, 1206 and 6261 native plant species have been used in Mesoamerica, the Central Andes and lowland South America, respectively. At least 1555, 428 and 742 are managed outside and inside food production systems, and at least 1148, 428 and 600 are cultivated, respectively, suggesting at least incipient domestication. Full native domesticates are more numerous in Mesoamerica (251) than the Andes (124) and the lowlands (45). This synthesis reveals that domestication is more common in the Neotropics than previously recognized and started much earlier than reliance on food production systems. Hundreds of ethnic groups had, and some still have, alternative strategies that do involve domestication, although they do not rely principally on food production systems, such as agriculture.