Central Asians are underrepresented in genomic research, limiting insights into their genetic history and disease risk. We established the Central Asian Genomic Diversity Project and sequenced whole genomes from 166 individuals across 20 Central Asian and Afghan Hazara groups. We identify marked differentiation driven by varying West/East Eurasian ancestry; Tajiks align with West Eurasians, Dungans with East Asians, and we report four geographically structured Turkic-related clusters, two Indo-European clines, and long-range migration events, including Siberian links in Hazaras and Sino-Tibetan ties in Dungans. Admixture dates cluster ∼650–1000 years ago, coinciding with the Song–Yuan era and Mongol expansion. We characterize distinct distributions of medically relevant variants and population-specific adaptation signatures across metabolic, immune, and neurological pathways, and illuminate shifts in subsistence practices correlated with trait-associated variation. We also detect Neanderthal-like and Denisovan-like segments that show group-specific associations with immunity, psychiatric risk, drug metabolism, and diabetes, underscoring the scientific imperative for a broader characterization of Central Asian evolutionary history and informing precision medicine.