Objective To evaluate the clinical efficacy of vericiguat combined with sacubitril/valsartan sodium in treating heart failure (HF) and to investigate its effects on myocardial injury markers and ventricular remodeling. Methods The clinical data of 92 patients with HF who visited the cardiovascular department of The Second Affiliated Hospital of Henan University of Science and Technology from August 2023 to August 2025 and met the inclusion and exclusion criteria were continuously included for analysis. According to the different treatment plans, the patients were divided into the control group (n＝46) and the study group (n＝46). The control group received Sacubitril/Valsartan Sodium Tablets, while the study group added Vericiguat Tablets to the control regimen. Clinical efficacy was compared between groups. Serum markers including cardiac troponin I (cTnI), myoglobin (Myo), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were monitored. Echocardiography assessed left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular end-systolic volume (LVESV). Results The overall clinical response rate was significantly higher in the study group than in the control group(P＜0.05). Post-treatment, serum levels of cTn I, Myo, and NT-proBNP were significantly reduced in the study group compared to the control group (all P＜0.05). Regarding cardiac function improvement, the study group demonstrated a significant increase in LVEF, and ventricular remodeling indicators including LVEDD, LVESD, and LVESV were superior to those in the control group(all P＜0.05). Conclusion The combination of vericiguat with sacubitril/valsartan sodium in the treatment of HF yields significant synergistic effects, enhances the overall clinical response rate, effectively reduces myocardial injury and HF serum biomarkers, and improves cardiac systolic function as well as structural remodeling. This regimen may serve as a therapeutic strategy to improve HF prognosis.