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The Warburg effect-induced lactate production in T-cell acute lymphoblastic leukemia (T-ALL) cell proliferation is well established, however, the role of lactate-mediated protein lactylation in this process remains poorly understood. In this study, we demonstrated that inhibiting lactate levels through the lactate dehydrogenase A (LDHA) inhibitor significantly reduced both cell proliferation and protein lactylation levels in T-ALL cells. Lactate deficiency led to a marked decrease in protein lactylation, accompanied by impaired cell proliferation. Meanwhile, lactate deficiency also induced the S‑phase cell cycle arrest and reduced DNA synthesis, which collectively impaired cell proliferation. Mechanistically, we observed that the decreased expression of lactylation in histone H3 at lysine 18 (H3K18lac) reduced the enrichment of this mark on the promoter region of neurotrophic receptor tyrosine kinase 3 (NTRK3), which supported the cell proliferation of T-ALL cells. Moreover, the overexpression of NTRK3 rescued the lactate deficiency-induced proliferation inhibition of T-ALL cells. Furthermore, exogenous lactate supplementation dramatically restored the decreased cell proliferation in T-ALL cells and restored H3K18lac levels. Our findings reveal a novel role of lactate-mediated protein lactylation in regulating T-ALL cell proliferation.