Macrophage activation is a hallmark of atherosclerosis, accompanied by a switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and histone modifications in macrophages is worthy of further investigation. Here, we find that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated histone lactylation is closely related to atherosclerosis. Histone H3 lysine 18 lactylation dependent on MCT4 deficiency activated the transcription of anti-inflammatory genes and tricarboxylic acid cycle genes, resulting in the initiation of local repair and homeostasis. Strikingly, histone lactylation is characteristically involved in the stage-specific local repair process during M1 to M2 transformation, whereas histone methylation and acetylation are not. Gene manipulation and protein hydrolysis-targeted chimerism technology are used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and histone modifications, plays a key role in training macrophages to become repair and homeostasis phenotypes. Display omitted •MCT4 is highly expressed in macrophages of atherosclerotic plaque•Macrophage MCT4 deficiency enhances p300-mediated histone lactylation•H3K18la initiates macrophage repair and promotes inflammatory resolution Zhang et al. show that MCT4 deficiency can enhance H3K18la level, which favors a reparative environment through improving anti-inflammatory activity and metabolic rewiring. They also show that administration of MCT4 inhibitors decreases atherosclerosis progression, demonstrating the therapeutic potential of MCT4 inhibitors in atherosclerosis.