Abnormal myocardial metabolism is the leading cause of diabetic cardiomyopathy (DCM). Astragalus polysaccharide (APS) combination with liposome nanoparticles (APS-nano) exhibits greater efficacy. Therefore, this study assessed regulatory effect of APS-nano on fatty acid translocase (FAT)/CD36. Fifty SD rats were assigned into control group, model group, APS group, APS-nano group, and FAT/CD36 inhibitor group (n =10, each group), followed by analysis of FAT/CD36 mRNA, protein levels, and glucocorticoid receptor expression. APS-nano group rats had highest level of insulin among all groups and lowest blood sugar. The content of Total cholesterol (TC), triglyceride (TG) and Free Fatty Acid (FFA) in APS-nano group was lower than APS and model groups (P = 0.000), with higher TC and FFA than control group (P <0.001), while insulin, blood sugar, TC, TG and FFA in the APS group were lower than model group (P = 0.000). FAT/CD36 mRNA in the model, APS, and APS-nano groups decreased to varying degrees (P <0.01). Administration of APS-nano greatly increased glucocorticoid receptor (P <0.01). APS-nano can regulate FAT/CD36 expression and improve fatty acid metabolism, thereby lowering myocardial tissue metabolism and inhibiting glucocorticoid receptor levels.