Determining the distribution of disease prevalence among heterogeneous populations at the national scale is fundamental for epidemiology and public health. Here, we use a combination of methods (spatial scan statistic, topological data analysis and epidemic profile) to study measurable differences in malaria intensity by regions and populations of Colombia. This study explores three main questions: What are the regions of Colombia where malaria is epidemic? What are the regions and populations in Colombia where malaria is endemic? What associations exist between epidemic outbreaks between regions in Colombia? Plasmodium falciparum is most prevalent in the Pacific Coast, some regions of the Amazon Basin, and some regions of the Magdalena Basin. Plasmodium vivax is the most prevalent parasite in Colombia, particularly in the Northern Amazon Basin, the Caribbean, and municipalities of Sucre, Antioquia and Cordoba. We find an acute peak of malarial infection at 25 years of age. Indigenous and Afrocolombian populations experience endemic malaria (with household transmission). We find that Plasmodium vivax decreased in the most important hotspots, often with moderate urbanization rate, and was re-introduced to locations with moderate but sustained deforestation. Infection by Plasmodium falciparum, on the other hand, steadily increased in incidence in locations where it was introduced in the 2009-2010 generalized epidemic. Our findings suggest that Colombia is entering an unstable transmission state, where rapid decreases in one location of the country are interconnected with rapid increases in other parts of the country.