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High biomass production potential, wide adaptability, low input requirement, and low environmental risk make switchgrass an economically and ecologically viable energy crop. The inherent variability in switchgrass productivity due to variations in soil and variety could affect the sustainability and eco-friendliness of switchgrass-based ethanol production. This study examined the soil and variety effects on these variables. Three locations in Mississippi were selected based on latitude and potential acreage. Using ALMANAC, switchgrass biomass yields were simulated for several scenarios of soils and varieties. The simulated yields were fed to IBSAL to compute energy use and CO2 emissions in various operations in the biomass supply chain. From the energy and emissions values, the sustainability and eco-friendliness of ethanol production were determined using net energy value (NEV) and carbon credit balance (CCB) as indicators, respectively. Soil and variety effects on NEV and CCB were analyzed using the Kruskal-Wallis test. Results showed significant differences in NEV and CCB across soils and varieties. Both NEV and CCB increased in the direction of heavier to lighter soils and on the order of north-upland, south-upland, north-lowland, and south-lowland varieties. Only north-upland and south-lowland varieties were significantly different because they were different in both cytotype and ecotype. Gaps between lowland and upland varieties were smaller in a dry year than in a wet year. The NEV and CCB increased in the direction of dry to wet year. From south to north, they decreased for lowland cytotypes but increased for upland cytotypes. Thus, the differences among varieties decreased northwards.