LEP-2a, previously obtained from Lachnum YM130 exopolysaccharide, was acetylated and benzoylated successfully, which were confirmed by FT-IR and C-13 NMR analyses. The derivatives were designated as ALEP-2a and BLEP-2a, respectively, and their respective degree of substitution were 0.220 and 0.574. Our study showed that LEP-2a and its derivatives treatments significantly increased the activities of SOD, GPx, CAT and decreased the level of MDA in heart of the diabetic mice, meanwhile, the levels of AGEs, hs-CRP, sICAM-1, NO and ET-1 in serum were markedly inverted. In addition, histopathological observation also showed that polysaccharide treatement alleviated myocardial structure disorder and confluent necrosis of cardiac muscle fibers in the diabetic mice, especially the 200 mg/kg dose ALEP-2a-treated and BLEP-2a-treated. The above results suggest that ALEP-2a and BLEP-2a can preferably maintain the levels of antioxidant enzymes and improve cardiovascular function in the diabetic mice. In conclusion, LEP-2a and its derivatives possess potent cardioprotective effect, supporting them as promising cardioprotective agents in diabetes mellitus.