Background <p>Heart rate control is one of the cornerstones of atrial fibrillation (AF) management and is recommended in all AF patients, even as background therapy for rhythm control. Both non-dihydropyridine calcium channel blockers and beta blockers are recommended as first choice rate control drugs, but no preference is given. Even though there are important differences in pharmacological mechanisms and side effects between these drugs, large randomized controlled trials are lacking. We aim to critically evaluate and synthesize the scientific evidence comparing calcium channel blockers and beta blockers.</p> Methods <p>A systematic review is conducted in four databases: MEDLINE, Embase, Web of Science, and Cochrane Central, collecting all original research published up until March 2025. Studies including patients with AF (P) treated with non-dihydropyridine calcium channel blockers (I) or beta blockers (C) reporting heart rate (O) or other key secondary outcomes such as major adverse cardiac and cerebrovascular events or mortality will be included. Titles and abstracts, as well as full texts, will be screened by two reviewers, and results will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Assessment of risk of bias is evaluated using the Cochrane Risk-of-Bias (RoB 2) tool for randomized controlled trials and the Risk Of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) tool for non-randomized studies. If sufficient homogeneous data are available, meta-analyses are performed.</p> Discussion <p>Current systematic reviews on rate control in AF have primarily focused on acute rate control using the intravenous administration of calcium channel blockers and beta blockers. However, systematic reviews comparing these two drug classes for long-term rate control are lacking, and current guidelines offer little guidance for choosing one drug over the other. This systematic review with meta-analysis will compare the effects of calcium channel blockers and beta blockers on heart rate and provide a comprehensive overview of clinical outcomes and side effects in the treatment of AF. It aims to provide a comprehensive overview, helping clinicians tailor rate control for individual patients.</p> Systematic review registration <p>PROSPERO CRD42024526695</p>