Significance Viruses are strong sources of natural selection pressure during human evolutionary history. Investigating genetic diversity and detecting signatures of natural selection at host genes related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection help to identify functionally important variation. We conducted a large study of global genomic variation at host genes that play a role in SARS-CoV-2 infection with a focus on underrepresented African populations. We identified nonsynonymous and regulatory variants at ACE2 that appear to be targets of recent natural selection in some African populations. We detected evidence of ancient adaptive evolution at TMPRSS2 in the human lineage. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with coronavirus disease 2019.