Author summary Despite major progress in malaria control or elimination in South America in the last years, this disease is still an important public health concern in all the Amazon basin countries, particularly during 2017 and 2018, when a substantial malaria incidence (similar to one million) was reported. Most of the rise in cases has been due to increases in malaria transmission in Venezuela. Within this country, populations in the southeastern (Guiana Shield) region have been at the highest risk of Plasmodium vivax and P. falciparum infection. In this study, reported malaria cases between 2007-2017 in this region were analyzed to stratify the spatial risk of disease and identify the malaria surge's main driver over the last years. Malaria risk was highly focal and prevalent in 2 consistent disease hotspots that accounted for most Plasmodium transmission in the whole region. Illegal gold-mining activities seem to drive malaria in these disease pockets and seem critical in malaria's surge throughout the country. Analyses of the Venezuelan surveillance data showed that from 2014 onwards, local malaria transmission has reemerged in new areas of the country, leading to a shift in this disease's epidemiology. Successful control of Venezuela's ongoing malaria epidemic requires hotspot-targeted control at the national level and regional coordination to avoid cross-border malaria spillover. Malaria elimination in Latin America is becoming an elusive goal. Malaria cases reached a historical similar to 1 million in 2017 and 2018, with Venezuela contributing 53% and 51% of those cases, respectively. Historically, malaria incidence in southern Venezuela has accounted for most of the country's total number of cases. The efficient deployment of disease prevention measures and prediction of disease spread to new regions requires an in-depth understanding of spatial heterogeneity on malaria transmission dynamics. Herein, we characterized the spatial epidemiology of malaria in southern Venezuela from 2007 through 2017 and described the extent to which malaria distribution has changed country-wide over the recent years. We found that disease transmission was focal and more prevalent in the southeast region of southern Venezuela where two persistent hotspots of Plasmodium vivax (76%) and P. falciparum (18%) accounted for similar to 60% of the total number of cases. Such hotspots are linked to deforestation as a consequence of illegal gold mining activities. Incidence has increased nearly tenfold over the last decade, showing an explosive epidemic growth due to a significant lack of disease control programs. Our findings highlight the importance of spatially oriented interventions to contain the ongoing malaria epidemic in Venezuela. This work also provides baseline epidemiological data to assess cross-border malaria dynamics and advocates for innovative control efforts in the Latin American region.