Background: Endoscopic carpal tunnel release (ECTR) and open carpal tunnel release (OCTR) both have advantages and disadvantages for the treatment of carpal tunnel syndrome (CTS). We compared the effectiveness and safety of ECTR and OCTR based on evidence from a high-level randomized controlled trial. Methods: We comprehensively searched PubMed, EMBASE, Cochrane Library, Web of Science, and Medline to identify relevant articles published until August 2019. Data regarding operative time, grip strength, Boston Carpal Tunnel Questionnaire scores, digital sensation, patient satisfaction, key pinch strength, return to work time, and complications were extracted and compared. All mean differences (MD) and odds ratios (OR) were expressed as ECTR relative to OCTR. Results: Twenty-eight studies were included in our meta-analysis. ECTR was associated with significantly higher satisfaction rates (MD, 3.13; 95% confidence interval [CI], 1.43 to 4.82; P = 0.0003), greater key pinch strengths (MD, 0.79 kg; 95% CI, 0.27 to 1.32; P = 0.003), earlier return to work times (MD, -7.25 days; 95% CI, -14.31 to -0.19; P = 0.04), higher transient nerve injury rates (OR, 4.87; 95% CI, 1.37 to 17.25; P = 0.01), and a lower incidence of scar-related complications (OR, 0.20; 95% CI, 0.07 to 0.59; P = 0.004). There were no significant differences between the two methods in terms of permanent nerve injury (OR, 1.93; 95% CI, 0.58 to 6.40; P = 0.28). Conclusions: Overall, evidence from randomized controlled trials indicates that ECTR results in better recovery of daily life functions than OCTR, as revealed by higher satisfaction rates, greater key pinch strengths, earlier return to work times, and fewer scar-related complications. Our findings suggest that patients with CTS can be effectively managed with ECTR.