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This study aims to explore the mechanism of Anshen Dingxin Granules in improving isoproterenol(ISO)-induced ventricular premature beats(VPB) in rats. Sixty rats were randomly divided into six groups: a control group, a model group, a low-dose Anshen Dingxin Granules group, a middle-dose Anshen Dingxin Granules group, a high-dose Anshen Dingxin Granules group, and a propranolol group. The control and model groups were given physiological saline. Two hours after gavage, ISO was injected to induce VPB in all groups except the control group. The injection continued for 7 days. Afterward, the VPB occurrence in each group was monitored by electrocardiogram. Histopathological changes in myocardial tissues were observed by HE and Masson staining. Ultrastructural changes in myocardial tissues were examined by transmission electron microscopy(TEM). The serum superoxide dismutase(SOD), malondialdehyde(MDA), and glutathione(GSH) levels were measured using biochemical methods. The hypoxia-inducible factor-1α(HIF-1α) protein expression in myocardial tissues was analyzed by immunohistochemistry. The HIF-1α, nuclear factor E2-related factor 2(Nrf2), heme oxygenase 1(HO-1), and glutathione peroxidase 4(GPX4) protein expressions in myocardial tissues were detected by Western blot. The Nrf2, HO-1, and GPX4 mRNA expressions in myocardial tissues were measured by PCR. The results show that, compared with the control group, the model group exhibits frequent VPBs and significantly increased arrhythmia scores(P<0.01), significantly increased heart weight index(HWI)(P<0.01), significant pathological damage in myocardial tissues, elevated levels of the oxidative stress marker MDA(P<0.01), and decreased SOD and GSH levels(P<0.01), increased HIF-1α protein expression(P<0.01), decreased Nrf2, HO-1, and GPX4 protein expressions(P<0.01), as well as decreased Nrf2, HO-1, and GPX4 mRNA expressions(P<0.01). Compared with the model group, the propranolol group and the high-dose Anshen Dingxin Granules group exhibit delayed onset and reduced frequency of VPBs(P<0.01). Besides, in the two groups of the above comparison, a significant decrease occurs as follows: arrhythmia scores(P<0.05), HWI(P<0.05 or P<0.01), myocardial tissue pathological damage, oxidative stress indicator MDA level(P<0.05 or P<0.01), HIF-1α protein expression(P<0.01) while significant increase is found in the items below: SOD and GSH levels(P<0.01), Nrf2, HO-1, and GPX4 protein expressions(P<0.05 or P<0.01), Nrf2, HO-1, and GPX4 mRNA expressions(P<0.05 or P<0.01). In conclusion, Anshen Dingxin Granules can improve ISO-induced VPB in rats. This effect may stem from HIF-1 signaling pathway regulation, which inhibits oxidative stress and in turn reduces myocardial cell damage.