Since pharmacological choices for patients with a failing systemic right ventricle (RV) in the context of transposition of the great arteries (TGA) following atrial switch or congenitally corrected TGA are not properly described, therefore, researchers sought to determine the feasibility as well as the impacts of sacubitril/valsartan therapy in a single-centre cohort of patients. Structural follow-up was performed in patients with a systemic RV ejection fraction of ≤ 35% who were symptomatic despite management with β-blocker and ACE-inhibitor/angiotensin II receptor-blockers and were initiated on sacubitril/valsartan. A significant reduction in N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) was evident. Small improvements were seen in echocardiographic systemic RV fractional area change and global longitudinal strain. In addition, there was a significant improvement in 6 min walking distance, from an average of 564 to 600 m. Improvements were also evident in quality of life domains of cognitive function, sleep and vitality. In this report of the first patient cohort with systemic RV failure managed with sacubitril/valsartan, findings indicated the feasibility of the treatment as well as showed its efficacy in terms of improving NT-pro-BNP and echocardiographic function. The potential of sacubitril/valsartan for this patient group was revealed by these positive findings.