The response of gamma delta (γδ) T cells in the acute versus chronic phases of the same infection is unclear. How γδ T cells function in acute Mycobacterium tuberculosis (Mtb) infection is well characterized, but their response during persistent Mtb infection is not well understood, even though most infections with Mtb manifest as a chronic, clinically asymptomatic state. Here, we analyze peripheral blood γδ T cells from a South African adolescent cohort and show that a unique CD8 ⁺ γδ T cell subset with features of “memory inflation” expands in chronic Mtb infection. These cells are hyporesponsive to T cell receptor (TCR)–mediated signaling but, like NK cells, can mount robust CD16-mediated cytotoxic responses. These CD8 ⁺ γδ T cells comprise a highly focused TCR repertoire, with clonotypes that are Mycobacterium specific but not phosphoantigen reactive. Using multiparametric single-cell pseudo-time trajectory analysis, we identified the differentiation paths that these CD8 ⁺ γδ T cells follow to develop into effectors in this infection state. Last, we found that circulating CD8 ⁺ γδ T cells also expand in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may drive similar γδ T cell effector programs and differentiation fates.