Objective To explore the effect of recombinant human brain natriuretic peptide (rh-BNP) combined with sacubitril/valsartan in patients with acute decompensated heart failure (ADHF). Methods A total of 86 patients with ADHF in Zhengzhou Orthopedic Hospital from March 2022 to August 2024 were selected as the research subjects and divided into the peptide group and the inhibitor group by the coin-tossing method. Both groups were given basic treatment. The peptide group was treated with rh-BNP, and the inhibitor group was treated with sacubitril/valsartan on the basis of the peptide group. The improvement of vital signs, cardiac function, levels of neuroendocrine hormones and N-terminal pro-brain natriuretic peptide (NT-proBNP), adverse reactions and prognosis were compared between the two groups. Results After 3 months of treatment in both groups, the respiratory rate, heart rate and systolic blood pressure levels decreased compared with those before treatment, and those in the inhibitor group were lower than those in the peptide group (P<0.05). After 3 months of treatment in both groups, the left ventricular ejection fraction (LVEF) levels increased compared with those before treatment, and the level in the inhibitor group was higher than that in the peptide group. The levels of left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic diameter (LVESD) decreased compared with those before treatment, and the inhibitor group was lower than the peptide group (P <0.05). After 3 months of treatment in both groups, the levels of NT-proBNP, endothelin-1 (ET-1) and norepinephrine (NE) decreased compared with those before treatment, and those in the inhibitor group were lower than those in the peptide group (P<0.05). By Fisher’s exact probability test, the incidence of adverse reactions in the inhibitor group was 13.95% (6/43), and the readmission rate after one month of treatment was 4.65% (2/43), which showed no difference compared with 6.98% (3/43) and 11.63% (5/43) in the peptide group (P>0.05). Conclusion The combined application can improve the vital signal conditions of patients with ADHF, regulate the levels of neuroendocrine hormones and NT-proBNP, and regulate cardiac function. It has certain safety and is conducive to the improvement of prognosis.