The origin of maize (Zea mays mays) in the US Southwest remains contentious, with conflicting archaeological data supporting either coastal 1-4 or highland 5,6 routes of diffusion of maize into the United States. Furthermore, the genetics of adaptation to the new environmental and cultural context of the Southwest is largely uncharacterized 7. To address these issues, we compared nuclear DNA from 32 archaeological maize samples spanning 6,000 years of evolution to modern landraces. We found that the initial diffusion of maize into the Southwest about 4,000 years ago is likely to have occurred along a highland route, followed by gene flow from a lowland coastal maize beginning at least 2,000 years ago. Our population genetic analysis also enabled us to differentiate selection during domestication for adaptation to the climatic and cultural environment of the Southwest, identifying adaptation loci relevant to drought tolerance and sugar content.