Esmolol has been proposed as a viable adjunctive therapy for pre-hospital refractory ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT). We performed a systematic review and meta-analysis to assess the effectiveness of esmolol on pre-hospital refractory VF/pVT, compared with standard of care. MEDLINE, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for eligible studies. Two investigators independently extracted relevant data and assessed the methodological quality of each included study using the ROBINS-I tool. The quality of evidence for summary estimates was assessed according to GRADE guidelines. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) for each outcome of interest were calculated. The search yielded 3253 unique records, of which two studies were found to be in accordance with the research purpose, totaling 66 patients, of whom 33.3% (n = 22) received esmolol. Additional evidence was provided in the paper but was not relevant to the analysis and was therefore not included. Esmolol was likely associated with an increased rate of survival to discharge (RR 2.82, 95% CI 1.01-7.93, p = 0.05) (GRADE: Very low) and survival with favorable neurological outcome (RR 3.44, 95% CI 1.11-10.67, p = 0.03) (GRADE: Very low). Similar results were found for return of spontaneous circulation (ROSC) (RR 2.63, 95% CI 1.37-5.07, p = 0.004) (GRADE: Very low) and survival to intensive care unit (ICU)/hospital admission (RR 2.63, 95% CI 1.37-5.07, p = 0.004) (GRADE: Very low). The effectiveness of esmolol for refractory VF/pVT remains unclear. Trial sequential analysis (TSA) indicates that the evidence is inconclusive and that further trials are required in order to reach a conclusion. Therefore, it is imperative to continue to accumulate evidence in order to obtain a higher level of scientific evidence.