The aim of this study was to investigate the protective effect of curcumin (Cu) on myocardial injury in diabetic cardiomyopathy in vivo and in vitro. Serum and myocardial glucose, inflammatory cytokines, and cardiac function indexes of type 2 diabetes db/db mice were measured. The mechanism of action was confirmed by immunohistochemistry, immunofluorescence, and western blot experiments. H9C2 cells stimulated by glucose (Glu) were used as cell models in vitro. Cu treatment improved glucose tolerance and lipid profile and reduced the production of inflammatory cytokines. In addition, Cu decreased the serum biochemical indexes. Cu inhibits high mobility group box 1 (HMGB1) signaling pathway in db/db mice. Cu treatment also significantly inhibited pa‐induced inflammatory signaling pathway in H9C2 cells. HMGB1 inhibitor or HMGB1 knockdown counteracted the effects of Cu on diabetic cardiomyopathy. The present study showed the protective effects of Cu on myocardial injury via HMGB1 pathway in diabetic cardiomyopathy in vivo and in vitro.