Objective: To investigate the effect of vericiguat combined with the “new quadruple therapy” on cardiac function and vascular endothelial indices in patients with coronary heart disease and heart failure with reduced ejection fraction (HFrEF). Methods: 108 patients with coronary heart disease and HFrEF admitted to our hospital from January 2024 to December 2025 were prospectively enrolled and randomly divided into a combination group and a control group using the envelope method, with 54 cases in each group. The control group received the “new quadruple therapy,” while the combination group received oral vericiguat in addition to the treatment of the control group. Cardiac function, vascular endothelial indicators, oxidative stress markers, and adverse reactions were compared between the two groups. Results: After treatment, the left ventricular ejection fraction in the combination group was greater than that in the control group (P<0.05), and the left ventricular end-diastolic diameter and left ventricular end-systolic diameter were smaller than those in the control group (P<0.05). After treatment, the levels of endothelin-1, malondialdehyde, and reactive oxygen species in the combination group were lower than those in the control group (P<0.05), while the levels of nitric oxide, vascular endothelial growth factor, and superoxide dismutase were higher than those in the control group (P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). Conclusion: Vericiguat in combination with the “new quadruple therapy”? drugs improves cardiac function and vascular endothelial function, promotes reverse ventricular remodeling, alleviates oxidative stress, and is safe and feasible in patients with coronary heart disease and heart failure with reduced ejection fraction (HFrEF).