Aim To study the protective effect of tetra-hydroxystilbeneglucoside ( TSG ) on cardiac injury and the mechanism involved in silent mating type informa-tion regulation 2 homolog 1 ( SIRT1 ) and adenosine monophosphate-activated protein kinase( AMPK) in the diabetic rats. Methods Type 2 diabetic rats were sac-rificed after administration with TSG for 8 weeks. Blood glucose, blood lipids, liverfunction,creatine ki-nase ( CK ) , lactate dehydrogenase ( LDH ) as well as myocardial nonesterified fatty acids( NEFA) were deter-mined by using biochemical test. The concentration of myocardial fatty acid transport proteins ( FATPs ) and-fatty acid β-oxidase ( FA-β-oxidase ) , and the levels of tumor necrosis factor alpha ( TNF-α) , interleukin -6 ( IL-6 ) , interleukin-1β( IL-1β) in serum were also measured by ELISA method and radio immunoassay re-spectively. The protein expressions of TNF-α, IL-6, IL-1β, SIRT1 and AMPK were detected by Western blot. Results Treatment of TSG reduced the contentof blood lipids, NEFA and collagen without affecting the content of blood glucose and insulin. The levels of TNF-α, IL-6 and IL-1βin serum as well as the protein expressions of TNF-α, IL-6 and IL-1β of cardia were also inhibited by administration with TSG. Treatment of TSG caused a significantly increased concentration of myocaidial FATPs and FA-β-oxidase, and dramatically restored the decreased protein expressions of SIRT1 and pAMPK in diabetic rats. Conclusion The protec-tive mechanisms of TSG against diabetic rats are in-volved in the alleviation of inflammatory mediator injury and improving energy metabolism.