In pre-hospital settings, efficient cardiopulmonary resuscitation (CPR) is challenging; therefore, the application of mechanical CPR devices continues to increase. However, the evidence of the benefits of using mechanical CPR devices in pre-hospital settings for adult out-of-hospital cardiac arrest (OHCA) is controversial. This meta-analysis compared the effects of mechanical and manual CPR applied in the pre-hospital stage on clinical outcomes after OHCA. Cochrane Library, PubMed, Embase, and ClinicalTrials.gov were searched from inception until October 2021. Studies comparing mechanical and manual CPR applied in the pre-hospital stage for survival outcomes of adult OHCA were eligible. Data abstraction, quality assessment, meta-analysis, trial sequential analysis (TSA), and grading of recommendations, assessment, development, and evaluation were conducted. Seven randomized controlled and 15 observational studies were included. Compared to manual CPR, pre-hospital use of mechanical CPR showed a positive effect in achieving return of spontaneous circulation (ROSC) and survival to admission. No difference was found in survival to discharge and discharge with favorable neurological status, with inconclusive results in TSA. In conclusion, pre-hospital use of mechanical CPR devices may benefit adult OHCA in achieving ROSC and survival to admission. With low certainty of evidence, more well-designed large-scale randomized controlled trials are needed to validate these findings.