Guizhi Gancao Decoction (GGD), a traditional Chinese medical recipe, has been widely used in the treatment of cardiovascular diseases in China for centuries. The present study was carried out to determine whether GGD exerts direct protective effects against pressure overload-induced heart failure. Moreover, we investigated whether GGD affects tubulin expression and posttranslational modifications. We demonstrated that GGD ameliorated TAC caused cardiac hypertrophy by gravimetric and echocardiography analysis in C57BL/6 mice. We found that GGD abrogated TAC-induced myocardium fibrosis by Masson's staining and collagen volume fraction (CVF) analysis. By using pressure-volume hemodynamic measurements, we found that GGD prevented TAC-induced cardiac systolic and diastolic dysfunction. Immunoblotting and immunofluorescent analysis revealed that GGD abrogated TAC-induced detyrosination and acetylation abnormalities on microtubules. Our present study demonstrated potential therapeutic effects of GGD against pressure overload-induced heart failure.