Decreased Na+/K+‐ATPase activity, and both sirtuin 1 (SIRT1) and adenosine monophosphate‐activated protein kinase (AMPK) have been reported to be involved in the development of diabetic cardiomyopathy (DCM). The present study aimed to investigate the advanced glycation end‐products (AGE) that impair Na+/K+‐ATPase stability by regulating the AMPK/SIRT1 pathway during progression of DCM. To study type 1 diabetic mellitus (T1DM), a disease model in rats was established by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg), and neonatal rat cardiomyocytes were also cultured. Heart function was detected by Doppler, and SIRT1 and AMPK protein expression were detected by immunohistochemistry and western blotting. Na+/K+‐ATPase activity was also monitored. Using in vivo rat models of DCM, we showed that Na+/K+‐ATPase activity decreased when both AMPK and SIRT1 expression were downregulated. In vitro, AGE impaired Na+/K+‐ATPase activity and decreased the AMPK and SIRT1 expression. Sirtuin 1 overexpression increased Na+/K+‐ATPase activity. 5‐aminoimidazole‐4‐carboxamide‐3‐ribonucleoside (AICAR) upregulated SIRT1 expression and increased Na+/K+‐ATPase activity, which could be partially abolished by splitomicin. Our results suggest that the dysfunction of DCM is related to AGE‐induced Na+/K+‐ATPase activity impairment through a mechanism involving the AMPK/SIRT1 pathway.