Background: Above one million annual hospitalizations occur with a primary diagnosis of acute heart failure in the US, with comparable numbers in Europe. Within 1 year, over a third of patients have died or been re-hospitalized. Most patients have acutely elevated systemic and/or intra-cardiac blood pressures as part of the acute heart failure syndrome. Most clinical trials of acute heart failure have aimed at reducing preload and/or afterload through drug-induced vasodilation. However, recent European guidelines downgraded the treatment recommendation of vasodilators. We aim to assess the beneficial and harmful effects of vasodilators in the treatment of acute heart failure. Methods: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We plan to include all randomized clinical trials assessing the use of vasodilators in the treatment of AHF. The systematic review will be conducted based on a systematic search of relevant major medical databases without date restrictions, including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) in addition to clinical trial registries. We will begin the searches in August 2022. All included trials will be assessed and classified at low risk of bias or at high risk of bias. Our conclusions will be based on the results from the primary outcomes with concomitant low risk of bias. Extracted data will be analyzed using Trial Sequential Analysis 0.9.5.10, Review Manager 5.3, and SAS. We will assess the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation. We will register this systematic review at Prospero and aim to update it when new trials are published. Discussion: This protocol defines the detailed methodology and approach used for a systematic review on whether vasodilation for acute heart failure improves patient outcome. This systematic review will potentially aid clinicians in deciding the optimal treatment of patients admitted with acute heart failure. Furthermore, this review will explore gaps in our knowledge and thus guide future research within acute heart failure.