There are very few objectively studied and proven medical interventions for the management of pediatric heart failure. Due to improvement in morbidity and mortality in the adult heart failure population, sacubitril/valsartan has started to be used in pediatric patients. The aim of this study was to characterize the acute cardiovascular effects of sacubitril/valsartan in the first 48 h after initiation. Single center retrospective study of pediatric patients in the cardiac intensive care unit who were initiated on sacubitril/valsartan for the first time over a three-year period. Clinical data was collected immediately prior to and within 48 h following initiation. A total of 16 patients with a mean age of 9.6 years were started on sacubitril/valsartan with a mean daily dose of 1.6 mg/kg/day in the first 48 h. Significant decreases were noted in N-terminal brain natriuretic peptide and vasoactive-inotrope score. No significant changes were noted in other clinical variables. The initiation of sacubitril/valsartan in a small cohort of pediatric patients with heart failure in the cardiac intensive care unit is associated with a significant decrease in N-terminal brain natriuretic peptide with a concurrent decrease in vasoactive-inotrope score and without significant change venous oxygen extraction ratio or other hemodynamic variables.