Great Scythia was the ancient Greek name for the area stretching from the northern Black Sea coast to the Middle Don. Using high-quality genomic data generated from 131 ancient individuals from Great Scythia and neighboring regions of the Bronze Age and the Iron Age, we established the genetic structure of the Scythians, revealing their diverse origin with major European Bronze Age ancestral components, and genetic traces of migration and invasions. We uncovered relationships between Scythians, including elite Scythians. Substantial endogamy in the Scythian clan was found. We examined Scythians’ phenotypes and medical-genetic background and found a harmful gene mutation causing fructose intolerance. This ancient “Scythian” mutation has spread throughout West Eurasia and has become the most prevalent genetic cause of fructose intolerance in contemporary European populations.