Abstract: Background: Coronary heart disease (CHD), characterized by impaired coronary artery function, often results in myocardial ischemia, hypoxia, and necrosis, with clinical manifestations such as angina pectoris. Vascular smooth muscle cell (VSMC) hypercontraction, primarily regulated by intracellular calcium (Ca²⁺), plays a central role in pathological coronary vasoconstriction. Purpose: This study aimed to evaluate the therapeutic effects of Huatuo Zaizao Pills (HTZZ) in alleviating myocardial ischemia due to abnormal coronary artery contraction and to elucidate the underlying molecular mechanisms. Methods: We conducted a double-blind, multicenter, randomized, placebo-controlled clinical trial to assess HTZZ's efficacy in patients with angina pectoris. In vivo, pituitrin-induced acute myocardial ischemia and spontaneously hypertensive rats (SHRs) were used to evaluate myocardial and vascular responses to HTZZ. In vitro, vasorelaxation mechanisms were investigated using isolated rat mesenteric arterial rings, patch clamp, calcium imaging, and ³H-ryanodine binding assays. Results: HTZZ significantly reduced the frequency and duration of angina attacks in clinical settings. It improved myocardial ischemia in mice and enhanced vascular elasticity and diastolic function in SHRs. Mechanistically, HTZZ induced vasodilation by inhibiting extracellular Ca²⁺ influx and reducing intracellular Ca²⁺ levels via suppression of L-type calcium channels (LTCCs) and ryanodine receptors (RyRs). Long-term HTZZ administration also downregulated LTCC expression at both protein and mRNA levels. Conclusion: HTZZ effectively alleviates angina and myocardial ischemia by suppressing Ca²⁺-mediated vasoconstriction through targeting LTCCs and RyRs. These findings highlight HTZZ as a promising therapeutic candidate for CHD characterized by coronary vasospasm and ischemia.