The Khoesan speakers are indigenous peoples in southern Africa, consisting of many different ethnic groups that do not speak Bantu languages. They are foragers with a complex history: they descended from the earliest diversification event for Homo sapiens, interacted with neighboring populations through migrations, and grappled with colonization. To investigate the Khoesan’s adaptation to their local environment, we analyzed genomic variations of Khoesan individuals with scans of natural selection, and identified variants that may be targets of selection in the Keratin (KRT) gene family. We examined a potential regulatory variant in KRT78, rs7307165, and conducted a dual luciferase reporter assay to determine if rs7307165 influenced gene expression. Results showed rs7307165 significantly affected enhancer activity in keratinocytes for KRT78. Missense mutations in KRT74 and KRT71 were also identified and appear to be compelling candidates for a mouse model experiment. Studying genetic variation in the Khoesan and other African populations can help us better understand human health, adaptation to local environments, and human history.