Heart failure (HF) is one of the most severe heart conditions, which lacks effective therapies. Therefore, it is necessary to develop more efficient drugs for HF. In this study, we investigated the cardioprotective effects of hyperoside against the pathological progression of HF. Thoracic aortic constriction (TAC) was performed to induce HF in rats. Hyperoside treatment improved cardiac function, decreased cardiomyocyte cross-sectional area and heart weight to body weight (HW/BW) ratio in HF rats. Moreover, hyperoside administration repressed apoptosis as evidenced by changing apoptosis-related protein levels, and promoted autophagy in TAC rats and angiotensin II (AngII)-induced H9C2 cells. Inhibition of autophagy by 3-methyladenine (3-MA) attenuated the beneficial effect of hyperoside against apoptosis in H9C2 cells. In summary, these data confirm that hyperoside effectively alleviates HF via suppressing apoptosis and inducing autophagy, which provides evidence that hyperoside may serve as a promising natural drug for treating HF.