Heart failure (HF) is the advanced heart disease with high morbidity and mortality. Compound DanShen Dripping Pill (CDDP) is a widely used Traditional Chinese Medicine for cardiovascular disease treatment. Herein, we investigated if CDDP can protect mice against doxorubicin (DOX) or isoprenaline (ISO)-induced HF. After 3 days feeding of normal chow containing CDDP, mice were started DOX or ISO treatment for 4 weeks or 18 days. At the end of treatment, mice were conducted electrocardiogram and echocardiographic test. Blood and heart samples were determined biochemical parameters, myocardial structure and expression of the related molecules. CDDP normalized DOX/ISO-induced heart weight changes, HF parameters and fibrogenesis. The DOX/ISO-impaired left ventricular ejection fraction and fractional shortening were restored by CDDP. Mechanistically, CDDP blocked DOX/ISO-inhibited expression of antioxidant enzymes and DOX/ISO-induced expression of pro-fibrotic molecules, inflammation and cell apoptosis. Additional DOX/ISO-impaired targets in cardiac function but protected by CDDP were identified by RNAseq, qRT-PCR and Western blot. In addition, CDDP protected cardiomyocytes against oxygen-glucose deprivation-induced injuries. Taken together, our study shows that CDDP can protect against myocardial injuries in different models, suggesting its potential application for HF treatment.