Crop domestication provided the calories that fueled the rise of civilization. For many crop species, domestication was accompanied by the evolution of weedy crop relatives, which aggressively outcompete crops and reduce harvests. Understanding the genetic mechanisms that underlie the evolution of weedy crop relatives is critical for agricultural weed management and food security. Here we use whole-genome sequences to examine the origin and adaptation of the two major strains of weedy rice found in the United States. We find that de-domestication from cultivated ancestors has had a major role in their evolution, with relatively few genetic changes required for the emergence of weediness traits. Weed strains likely evolved both early and late in the history of rice cultivation and represent an under-recognized component of the domestication process. Genomic regions identified here that show evidence of selection can be considered candidates for future genetic and functional analyses for rice improvement.