Device closure is the first-line treatment for most atrial septal defects (ASDs). Minimally invasive cardiac surgery (MICS) has been found safe and effective for ASD closure with comparable mortality/morbidity and superior cosmetic results compared to conventional median sternotomy. Our goal was to compare percutaneous versus MICS of ASDs. A systematic review was performed using PubMed and the Cochrane Library (end-of-search date on May 22, 2019). Meta-analyses were conducted using fixed and random effects models. In the present systematic review, we analyzed six studies including 1577 patients with ASDs who underwent either MICS (n = 642) or device closure (n = 935). Treatment efficacy was significantly higher in the MICS (99.8%; 95% CI 98.9-99.9) compared to the device closure group (97.3%; 95% CI 95.6-98.2), (OR 0.1; 95% CI 0.02-0.6). Surgical patients experienced significantly more complications (16.2%; 95% CI 13.0-19.9) compared to those that were treated with a percutaneous approach (7.1%; 95% CI 5.0-9.8), (OR 2.0; 95% CI 1.2-3.2). Surgery was associated with significantly longer length of hospital stay (5.6 ± 1.7 days) compared to device closure (1.3 ± 1.4 days), (OR 4.8; 95% CI 1.1-20.5). Residual shunts were more common with the transcatheter (3.9%; 95% CI 2.7-5.5) compared to the surgical approach (0.95%; 95% CI 0.3-2.4), (OR 0.1; 95% CI 0.06-0.5). There was no difference between the two techniques in terms of major bleeding, hematoma formation, transfusion requirements, cardiac tamponade, new-onset atrial fibrillation, permanent pacemaker placement, and reoperation rates. MICS for ASD is a safe procedure and compares favorably to transcatheter closure. Despite longer hospitalization requirements, the MICS approach is feasible irrespective of ASD anatomy and may lead to a more effective and durable repair.