Metabolites play critical roles in macrophage polarization and in their function in response to infection and inflammation. α-aminobutyric acid (AABA), a non-proteinogenic amino acid which can be generated from methionine, threonine, serine, and glycine, has not been studied extensively in relation to macrophage polarization and function. In this study, we aimed to investigate the immunomodulatory function of AABA in regulating M1 macrophage polarization and function in vitro and in vivo. We stimulated bone-marrow-derived macrophages with lipopolysaccharide (LPS) to generate M1 macrophages. Subsequently, we induced sepsis and colitis in mice, followed by treatment with AABA. We then analyzed the samples using ELISA, real-time PCR, Western blotting, flow cytometry, and histopathological analysis to evaluate cytokine secretion, inflammatory gene expression, macrophage activation, disease progression, and inflammation severity. Additionally, metabolomic and chromatin immunoprecipitation-qPCR were conducted to investigate the function of AABA on metabolic reprogramming and epigenetic modifications of M1 macrophages. Our results revealed that AABA inhibited M1 macrophage polarization and function, which led to prolonged survival in septic mice and reduced disease severity in colitis mice. Mechanically, AABA promoted oxidative phosphorylation (OXPHOS) and glutamine and arginine metabolism while inhibiting glycolysis. Moreover, AABA could increase the occupancy of trimethylation of histone H3K27 at the promoter regions of M1 macrophage-associated inflammatory genes, which contributed to the inhibition of M1 macrophage polarization. These findings suggest that AABA may have therapeutic potential for inflammatory diseases by regulating macrophage polarization and function through metabolic and epigenetic pathways.