We present the Eco-ISEA3H database, a compilation of global spatial data characterizing climate, geology, land cover, physical and human geography, and the geographic ranges of nearly 900 large mammalian species. The data are tailored for machine learning (ML)-based ecological modeling, and are intended primarily for continental- to global-scale ecometric and species distribution modeling. Such models are trained on present-day data and applied to the geologic past, or to future scenarios of climatic and environmental change. Model training requires integrated global datasets, describing species’ occurrence and environment via consistent observational units. The Eco-ISEA3H database incorporates data from 17 sources, and includes 3,033 variables. The database is built on the Icosahedral Snyder Equal Area (ISEA) aperture 3 hexagonal (3H) discrete global grid system (DGGS), which partitions the Earth’s surface into equal-area hexagonal cells. Source data were incorporated at six nested ISEA3H resolutions, using scripts developed and made available here. We demonstrate the utility of the database in a case study analyzing the bioclimatic envelopes of ten large, widely distributed mammalian species.