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Objective: Heart failure (HF), a worldwide health condition, is the result of many cardiovascular diseases. The traditional Chinese medicine (TCM) Xiaoyu Jiangzhi capsule (XYC) has long been in use in China to treat hyperlipidemia and inhibit platelet aggregation. This study explores the effects of XYC on heart failure (HF) and its detailed mechanisms. Methods: Isoproterenol (ISO, 30 mg/kg) was injected intraperitoneally for 7 days to copy a HF model of 10–12 weeks old, 20–30 g male mice. We then compared the CON (control) group, ISO (HF model) group, MET (metoprolol) group, and XYC group. Cardiac systolic function and left wall thickness were evaluated by echocardiograph. Using western blot analysis, we detected the proteins of calmodulin dependent protein kinase II (CaMKII) and sarco/endoplasmic reticulum Ca2+-ATPase (Serca). Furthermore, tsA201 cells were cultured and the human CaV1.2 calcium channel current (hCaV1.2) were detected by patch clamp experiments. Results: XYC reduced HF, inhibiting the protein expression of CaMKII, but Serca did not change significantly. Moreover, XYC inhibited the peak amplitude of the hCaV1.2 current, depolarizing shifted the activation curve 27.6 mV, and shifted the inactivation curve toward a positive potential 17.6 mV. The fraction recovered from inaction was reduced in XYC group compared with that in CON group. Conclusion: XYC could inhibit ISO-induced HF by reducing the Ca2+/CaMKII signaling pathway in mice.