The quality of a myocardial protection of a single-dose del Nido cardioplegia versus multiple dose blood-based cardioplegia on myocardial injury, outcomes and operative times in patients undergoing minimally invasive aortic valve replacement is basically unreported. Preoperative and post-operative data, as well as technical details from isolated minimally invasive aortic valve replacements, performed using single-dose or multiple-dose cardioplegia were prospectively collected and retrospectively analysed. A total of 110 patients undergoing minimally invasive valve replacements at our institution composed two groups: 55 patients in the blood cardioplegia group (BloCa) and 55 in the del Nido group (DeNiCa). The two-matched groups were comparable in terms of preoperative variables. In the DeNiCa group, there was a statistically significant less need for cardiac defibrillation after aortic cross-clamp release (p < 0.001). Moreover, the BloCa group received intraoperatively more blood transfusions (p = 0.001) and more insulin administration for higher glucose levels (p < 0.001). The BloCa group showed higher intraoperative lactate levels (p = 0.01). Need for post-operative inotropic and vasoactive support, Creatine Kinase-MB levels after 6 and 12 h, onset of post-operative atrial fibrillation and length of stay were similar. No deaths occurred in neither groups. Single-dose del Nido cardioplegia in the setting of minimally invasive aortic surgery seems to offer adequate myocardial protection, comparable to multiple dose hematic cardioplegia. It has been documented a lower peri-operative need of defibrillation after cross-clamp release, lactate- and glucose peak values, as well as less blood transfusions compared to blood cardioplegic strategy.