INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) is a leading cause of global mortality. Timely drug administration via vascular access is critical, with intravenous (IV) and intraosseous (IO) routes being the primary options. Current guidelines prefer IV access but recommend IO when IV access is delayed. This systematic review and meta-analysis of randomized controlled trials (RCTs) evaluated the clinical effectiveness of IO compared to IV access in adults with OHCA. METHODS: A comprehensive search of PubMed, Scopus, and Cochrane databases through November 2024 identified RCTs comparing IO and IV drug administration in OHCA patients aged ≥18 years. Outcomes included 30-day survival, sustained return of spontaneous circulation (ROSC), survival to hospital discharge, and survival with favorable neurological outcomes. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Three RCTs comprising 9293 patients were included. No significant differences were found between IO and IV routes for 30-day survival (OR: 1.00, 95 % CI: 0.76-1.34, p = 0.98), sustained ROSC (OR: 1.08, 95 % CI: 0.97-1.21, p = 0.18), survival to hospital discharge (OR: 1.03, 95 % CI: 0.84-1.25, p = 0.80), or favorable neurological outcomes (OR: 0.93, 95 % CI: 0.77-1.13, p = 0.49). CONCLUSION: IV and IO access routes demonstrated comparable outcomes for survival and neurological function in OHCA. These findings support the flexibility to prioritize the most practical route in emergency settings, particularly when IV access is delayed or challenging. Further research should explore patient-level outcomes and health economic implications.