The objectives of this research were to investigate the fermentation performance of US sorghum varieties for the production of distilled spirits as well as their associated coproducts and to study the formation of volatile compounds that are related to the flavor quality of the spirits. Three US sorghum varieties (red, white, and waxy sorghums) and four yeast strains (DADY, Ethanol Red, GR-2, and 71B) were used for distilled spirit production. Both sorghum variety and type of yeast strains had effects on alcohol concentration and alcohol yield. The alcohol concentration varied from 10.26 to 11.34% (v/v) while alcohol yield varied from 80.93 to 90.33%. Using Ethanol Red yeast achieved consistently the highest average alcohol concentration (11.10%, v/v) and yield (87.33%) regardless of variation in sorghum variety. Waxy sorghum demonstrated significantly higher average alcohol concentration (11.20%, v/v) and yield (89.65%) than white sorghum (10.74% for concentration and 84.7% for yield) and red sorghum (10.28% for concentration and 82.27% for yield). Alcohol fermentation also produces other metabolites as byproducts. Glycerol and lactic acid are the two major byproducts found from sorghum spirit fermentation. DADY produced the highest level of glycerol (∼1.4–1.5%, v/v) during fermentation, while GR-2 produced the lowest level of glycerol (0.9–1.1%, v/v). For all conditions, the lactic acid level was less than 1.2% (v/v). Eight volatile compounds were identified in sorghum spirits which mainly relate to fruity, sour, sweet, floral, buttery, and creamy flavors of the spirits