Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The Vδ2+ subset of γδ T cells possess intrinsic reactivity to malaria antigens, can mediate killing of P. falciparum merozoites, and expand markedly in vivo following malaria infection in previously naïve hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated γδ T cell responses to malaria among 4-year-old children enrolled in a longitudinal study in Uganda. We found that repeated malaria was associated with reduced percentages of Vδ2+ γδ T cells in peripheral blood, decreased proliferation and cytokine production in response to malaria antigens, and increased expression of immunoregulatory genes. Further, loss and dysfunction of pro-inflammatory Vδ2+ γδ T cells was associated with a reduced likelihood of symptoms upon subsequent P. falciparum infection. Together, these results suggest that repeated malaria infection during childhood results in progressive loss and dysfunction of Vδ2+ γδ T cells that may facilitate immunological tolerance of the parasite.