The botanical knowledge of Mapuche people settled on the peripheries of Esquel city (Argentine Patagonia) was compared with that of urban residents in order to know their particularities, and to understand how rural–urban (rurban) hybridization resignifies their practices and medicinal plants richness for better adaptation to city life. Interviews were conducted with a sample of 79 patients attending primary health care centers (33 rurban Mapuches, 46 urban), and data were qualitative–quantitatively analyzed. Rurban residents cite similar plant richness to that of urban ones (∼69 species), though they are different in composition. Local medicinal flora provides responses to diseases with a similar incidence in both groups, but each group addresses them based on the resources it recognizes as most effective and accessible. The rurban system is flexible facing the challenge that life in the city implies, evidencing the incorporation and replacement of native resources by exotic ones as an expression of restructuring processes and cultural diversification. These changes allow for recreation of memory about the importance of medicinal plants, and adjustment of therapeutic practices to a present time, having different needs from those of rurality. Urban residents incorporate plants from Mapuche pharmacopoeia, some of which are on visualization, evidencing bidirectional resource and ethnobotanical knowledge transference between groups. As a conclusion, this case study points out the importance of recognizing rurbanity as a starting point for the establishment of public policies that improve governance and access to health for Mapuche migrants in the city.