The temporal and spatial evolution of malaria was described for the postfrontier phase of the Brazilian Amazon in 2003-2013. The current ecological study aimed to understand the relationship between spatial population mobility and the distribution of malaria cases. The study identified epidemiologically relevant areas using regional statistical modeling and spatial analyses that considered differential infections and types of work activities. Annual parasite incidence (API) in the region was highest in hotspots along the Amazon River and in the south and west settlement zone of Hiléia, with concentrations in environmental protection areas and açaí and Brazil nut extraction areas. The dispersal force decreased in the Central Amazon due to rapid urbanization and improved socioeconomic conditions for workers in consolidated settlement areas. The study characterized the spatial patterns of disease transmission according to the economic activity and regionalization of geographic areas, confirming that the incidence of infection by work activity and labor flow is linked to extractive activities and agricultural settlements.