Background <p>The effect of vasodilators in the management of heart failure (HF) remains inconclusive. This study aims to evaluate and compare the overall benefits of vasodilators to patients with HF.</p> Methods <p>PubMed, Embase, Cochrane Library, and Web of Science were searched from database inception to December 27th, 2021. Randomized controlled trials (RCTs) assessing the efficacy of vasodilators in the treatment of HF were included. The Cochrane risk of bias assessment tool was applied to assess the risk of bias of included studies. Meta-analysis was performed using R and Stata 15.0 software.</p> Results <p>A total of 5517 articles were retrieved, and 18 eligible RCTs were finally included, with 9188 participants. Network meta-analysis showed no difference in the mortality, readmission rate, incidence of adverse cardiovascular events, and serum creatinine (Scr) among different vasodilators. Urapidil was more effective in reducing NT-pro-BNP, compared with nitroglycerin [WMD=-975.64, 95%CI (-1558.32, -320.14)].</p> Conclusion <p>There are no differences in the efficacy and safety among vasodilators in the management of HF. Especially, although nitroprusside may be the most effective in reducing mortality, there is no significant difference between other drugs. Given the low certainty of the evidence, current evidence suggests that vasodilators have limited efficacy in the routine management of HF. More well-designed RCTs are needed to validate these findings.</p> Trial registration <p>PROSPERO (CRD42022351231).</p>