Objective. To determine the influence of Entresto on clinical symptoms, ventricular remodeling (VR), and economic stress of patients with both acute myocardial infarction (AMI) and acute heart failure (AHF). Methods. Totally 120 patients with AMI complicated with AHF admitted to our hospital between January 2017 and August 2019 were enrolled and randomly assigned to an observation group (obs group) and a control group (con group) (each n = 60). The obs group was treated with Entresto, while the other with angiotensin-converting enzyme inhibitors (ACEI). After treatment, the efficacy on both groups was evaluated, and their cardiac function-associated indexes (left ventricular end-systolic diameter (LVESd), left ventricular end-diastolic dimension (LVEDd), left ventricular ejection fraction (LVEF), VR-associated indexes (interventricular septal thickness (IVST), and left ventricular mass index (LVMI)) were determined and compared before treatment and after 1 month of treatment. Additionally, their NT-pro-BNP, CRP, and TNF-α were tested and compared before and after treatment, and they were also compared in hospitalization time, treatment expense, readmission rate within one year after discharge, and adverse events. Results. After treatment, the obs group showed notably higher efficacy than the con group ( P < 0.05 ). Before treatment, the two groups were not greatly different in LVESd, LVEDd, LVEF, IVST, LVMI, NT-pro BNP, CRP, and TNF-α (all P > 0.05 ), while after treatment, these indexes of both groups were improved, but the improvement in the obs group was more notable ( P < 0.05 ). Additionally, the hospitalization time, treatment expense, readmission rate one year after discharge, and incidence of adverse events in the obs group were notably lower (all P < 0.05 ). Conclusion. For patients with both AMI and AHF, Entresto can contribute to strong amelioration of their clinical symptoms and prognosis and ventricular reverse-remodeling, with a high safety, so it is worthy of clinical promotion.