The agricultural revolution is a significant turning point in human history. Its effects are still deeply felt on many aspects of humankind’s social, political, and economic development. For the first time, this study empirically examines the birth of agriculture and identifies the global extinction of megafauna (large mammals) in the past 100,000 years as a paramount related event. During the ice ages, humans and plants heavily depended on megafauna for survival. Megafauna’s decreased abundance shifted human subsistence strategies toward more control over vital common resources. These strategies, in turn, underpinned the type of coevolutionary interactions between humans, animals, and plants that eventually resulted in domestication. The severity of extinction varied considerably in regions occupied by hominins (different species of humans) at different times over the past seven million years. Extinctions were negligible in Africa, moderate in Asia, and severe in the New World. Regression analyses of these exogenous differences reveal a non-monotonic effect of extinction on agriculture. Agriculture was most likely to emerge independently in the lower latitudes of Asia. All other regions experienced suboptimal extinction events, which had varying effects on the birth of agriculture.