Despite ongoing efforts for elimination, malaria continues to be a major public health problem in the Republic of Panama. For effective elimination, it is key that malaria foci and areas of high transmission are identified in a timely manner. Here, we study malaria transmission records for the 2015–2022 period, a time when cases have increased by a factor of ten. Using several methods to study spatial and spatiotemporal malaria confirmed case clusters at the level of localities, including LISA and scan, we found that cases are clustered across indigenous villages located within the autonomous indigenous regions of Ngäbe–Buglé, Guna Yala, and Embera, with the latter on the eastern border of Panama (with Colombia). We discuss the different factors that might be shaping the marked increase in malaria transmission associated with these clusters, which include an inflow of malaria-exposed migrating populations hoping to reach the USA, insufficient health services, and the lack of culturally sensitive actionable tools to reduce malaria exposure among the ethnically diverse and impoverished indigenous populations of Panama.