Chronic, low‑grade inflammation associated with obesity and diabetes result from the infiltration of adipose and vascular tissue by immune cells and contributes to cardiovascular complications. Despite an incomplete understanding of the mechanistic underpinnings of immune cell differentiation and inflammation, O‑GlcNAcylation, the addition of O‑linked N‑acetylglucosamine (O‑GlcNAc) to cytoplasmic, nuclear and mitochondrial proteins by the two cycling enzymes, the O‑linked N‑acetylglucosamine transferase (OGT) and the O‑GlcNAcase (OGA), may contribute to fine‑tune immunity and inflammation in both physiological and pathological conditions. Early studies have indicated that O‑GlcNAcylation of proteins play a pro‑inflammatory role in diabetes and insulin resistance, whereas subsequent studies have demonstrated that this post‑translational modification could also be protective against acute injuries. These studies suggest that diverse types of insults result in dynamic changes to O‑GlcNAcylation patterns, which fluctuate with cellular metabolism to promote or inhibit inflammation. In this review, the current understanding of O‑GlcNAcylation and its adaptive modulation in immune and inflammatory responses is summarized.