In clinical practice, Astragali Radix (Astragalus), the root of Astragalus membranaceus Bunge, has been widely applied to treat patients with viral diseases, including viral myocarditis in China. The present study was designed to evaluate the protective effects of Astragalus on the function of sarcoplasmic reticulum calcium ATPase (SERCA2) activity and endothelin system at acute and chronic periods of myocarditis mice induced by CVB(3) infection. Astragalus feeding (2.2 mg/kg/day) could significantly increase the survival rate, alleviate pathological alterations and serum cardiac troponin I (cTnI), as well as restore impaired SERCA activity at the acute stage. Low affinity and capacity of ETR were reversed with Astragalus after the first CVB(3) inoculation up to 7 days and after the second virus inoculation up to 150 days. In the meantime, the contents of cardiac ET-1 and ANP were reduced. Comparison the myocarditis mice treated with Perindopril (0.44 mg/kg/day), an ACE inhibitor, shows that Astragalus achieved a similar effect on survival rate, SERCA2 and ET system. These results indicated that the beneficial effects of Astragalus and Perindopril for treating viral myocarditis might be partly mediated by preserving the functions of SERCA 2 activity and ET system.