Purpose <p>Diabetic patients have a significantly higher incidence and faster progression of atherosclerosis than non-diabetic individuals, and abnormal macrophage lipophagy is a key pathological driver. This review aims to clarify the synergistic mechanisms of the hexosamine biosynthetic pathway (HBP) and fatty acid β-oxidation (FAO) in regulating macrophage lipophagy and promoting diabetic atherosclerosis, and to explore potential intervention strategies.</p> Methods <p>We systematically reviewed the molecular mechanisms and interactions of HBP and FAO in diabetic macrophages, focusing on their roles in lipophagy dynamic regulation and foam cell formation, as well as the crosstalk between HBP and FAO in metabolic reprogramming.</p> Results <p>HBP activation in the diabetic environment inhibits lipophagy-related molecules via O-GlcNAc modification, while FAO imbalance causes energy metabolism disorders, which synergistically exacerbate lipophagy dysfunction, promote macrophage-to-foam cell differentiation, and accelerate atherosclerotic plaque progression.</p> Conclusion <p>The synergistic dysfunction of HBP and FAO is a critical pathological link in diabetic atherosclerosis. Targeted regulation of these two pathways represents a promising intervention strategy, providing a theoretical basis and innovative ideas for the prevention and treatment of diabetes-related atherosclerosis.</p>