Paroxysmal supraventricular tachycardia (PSVT) treatment requires medically supervised intervention. Etripamil is a novel short-acting calcium channel blocker. Its intranasal spray formulation has a rapid onset of action and shows promise for the unsupervised treatment of PSVT. We aimed to evaluate the efficacy and safety of etripamil nasal spray for the acute conversion of PSVT. A systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching the PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane databases through to 1 December 2022. RevMan version 5.4 software was used to pool dichotomous outcomes using risk ratio (RR) presented with the corresponding confidence interval (CI). Three RCTs with a total of 496 participants were included in our analysis. Etripamil was effective for PSVT conversion at 15min (RR 1.84, 95% CI 1.37-2.48), 30min (RR 1.86, 95% CI 1.42-2.44), and 60min (RR 1.25, 95% CI 1.05-1.50) after drug administration; decreasing medical intervention-seeking (RR 0.58, 95% CI 0.37-0.90); and decreasing emergency room (ER) visits (RR 0.61, 95% CI 0.38-0.97). However, there was no difference at 300min (RR 1.10, 95% CI 0.97-1.25) and it was associated with higher rates of adverse events (RR 3.17, 95% CI 2.15-4.69). Etripamil nasal spray was effective and well tolerated to induce PSVT termination for up to 60min. Therefore, etripamil nasal spray constitutes a promising strategy for PSVT self-termination without medical supervision; however, further RCTs are required before endorsement in clinical practice.