Objective Del Nido cardioplegia (DC) has been used extensively in pediatric cardiac surgery but the efficacy and safety in adults remains uncertain. Our objective was to perform a systematic review and meta-analysis comparing DC and blood cardioplegia (BC) in our primary endpoint of 30-day or in-hospital mortality as well as other efficacy and safety endpoints. Methods Both MEDLINE and EMBASE were searched from 1996 to 2017 for studies comparing DC and BC. Data were extracted by 2 independent investigators and aggregated in a random effects model. Results One randomized controlled trial (n = 89), 7 adjusted (n = 1,104), and 5 unadjusted observational studies (n = 717) were included. There was no difference in in-hospital mortality between DC and BC (relative risk:0.67, 95% confidence interval CI: 0.22, 2.07; P = 0.49). DC reduced cardioplegia volume requirements (mean difference MD:−1.1 L, 95% CI, −1.6, −0.6; P < 0.0001), aortic cross-clamp time (MD: −8 minutes, 95% CI, −12, −3; P = 0.0004), and cardiopulmonary bypass (CPB) times (MD: −8 minutes, 95% CI, −14, −3; P = 0.03). DC reduced troponin release (standardized MD: −0.3, 95% CI, −0.5, −0.1; P = 0.001). In-hospital outcomes of stroke, atrial fibrillation, acute kidney injury/dialysis, low cardiac output state, blood transfusion, reoperation rate, postoperative left ventricular EF, intensive care unit length of stay (LOS), and in-hospital LOS were comparable between groups. Conclusions DC is a safe alternative to BC in routine adult cardiac surgery. Its use is associated with reduction in CPB and aortic cross-clamp times and may potentially offer improved myocardial protection.