BACKGROUND: Despite global intervention efforts, malaria remains a major public health concern in many parts of the world. Understanding geographic variation in malaria patterns and their environmental determinants can support targeting of malaria control and development of elimination strategies. METHODS: We used remotely sensed environmental data to analyze the influences of environmental risk factors on malaria cases caused by Plasmodium falciparum and Plasmodium vivax from 2014 to 2017 in two geographic settings in Ethiopia. Geospatial datasets were derived from multiple sources and characterized climate, vegetation, land use, topography, and surface water. All data were summarized annually at the sub-district (kebele) level for each of the two study areas. We analyzed the associations between environmental data and malaria cases with Boosted Regression Tree (BRT) models. RESULTS: We found considerable spatial variation in malaria occurrence. Spectral indices related to land cover greenness (NDVI) and moisture (NDWI) showed negative associations with malaria, as the highest malaria rates were found in landscapes with low vegetation cover and moisture during the months that follow the rainy season. Climatic factors, including precipitation and land surface temperature, had positive associations with malaria. Settlement structure also played an important role, with different effects in the two study areas. Variables related to surface water, such as irrigated agriculture, wetlands, seasonally flooded waterbodies, and height above nearest drainage did not have strong influences on malaria. CONCLUSION: We found different relationships between malaria and environmental conditions in two geographically distinctive areas. These results emphasize that studies of malaria-environmental relationships and predictive models of malaria occurrence should be context specific to account for such differences.