Several guidelines have recommended the use of angiotensin receptor neprilysin inhibitors (ARNIs) as replacement for angiotensin-converting enzyme inhibitors in the management of heart failure. Till date, there are no reviews done that comprehensively cover different aspects of efficacy and safety parameters. Hence, we have performed a comprehensive systematic review and meta-analysis on role of ARNIs for the management of heart failure patients. Searches were done in Embase, Scopus, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, PubMed Central, Cochrane Library, MEDLINE, Google Scholar, ScienceDirect and Clinicaltrials.gov until June 2022. Risk of bias assessment was done with Cochrane’s risk of bias tool. Meta-analysis was carried out using random-effects model. Pooled standardized mean difference (SMD)/mean difference (MD) and/or risk ratio (RR) with 95% confidence intervals (CIs) was reported. In total, we analysed 34 studies, with almost all of them had a high risk of bias. Pooled RR was 0.88 (95% CI: 0.82–0.95) for all-cause mortality, 0.84 (95% CI: 0.77–0.92) for cardiovascular mortality and 0.78 (95% CI: 0.70–0.87) for hospitalization. Pooled MD was 3.74 (95% CI: 1.93–5.55) for left ventricular ejection fraction, −2.16 (95% CI: −3.58 to −0.74) for left atrial volume index, −3.80 (95% CI: −6.60 to −1.00) for left ventricular end-diastolic dimension and −1.16 (95% CI: −1.98 to −0.35) forE/E′ ratio. Regarding adverse events, pooled RR was 1.55 (95% CI: 1.31–1.85) for symptomatic hypotension, 0.93 (95% CI: 0.78–1.11) for worsening renal function, 1.09 (95% CI: 0.94–1.26) for hyperkalaemia and 1.29 (95% CI: 0.67–2.50) for angioedema. ARNIs had beneficial efficacy and safety profile on the management of heart failure especially patients with reduced ejection fraction.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10741-022-10273-3.