BACKGROUND: Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), shows promising result in treating resistant hypertension (RH) but lacks comprehensive evaluation. We performed a systematic review to assess and compare the efficacy of ARNI in managing RH. METHODS: We conducted a systematic search on multiple databases such as Cochrane, ProQuest, PubMed, and Google Scholar. Studies comparing the effects of ARNI on blood pressure in adult RH patients were included in the review. Data extraction and synthesis followed PRISMA guidelines, and the risk of bias was assessed using Cochrane tools. The primary outcome is to determine the effect of ARNI on blood pressure in RH patients, and the secondary outcome was to assess the safety of ARNI in RH patients. RESULTS: Four studies involving 915 RH patients were included in the systematic review. The sacubitril/valsartan dose used ranged between 100 and 400 mg/day. All studies reported a statistically significant reduction in blood pressure, with 24-h blood pressure reduction ranging from 15.8/6.5 to 16.6/9.3 mmHg and office systolic blood pressure reduction ranging from 24.7 to 10.3 mmHg. Additionally, two studies reported improvements in cardiac remodeling and left ventricular function associated with sacubitril/valsartan. The most common adverse events were hypotension and elevated serum potassium levels, though these were minimal and did not require discontinuation of ARNI therapy. CONCLUSION: Sacubitril/valsartan is a promising alternative to ARB or ACEi in managing RH, offering superior blood pressure reductions and potential benefits in reversing cardiac remodeling, while maintaining a favorable safety profile with minimal risk of serious adverse events.