Objective: Del Nido cardioplegia solution provides a depolarized hyperkalemic arrest lasting up to 60 minutes. Single-dose del Nido cardioplegia solution may offer an alternative myocardial protection strategy to conventional whole blood cardioplegia following acute aortic dissection surgery. Methods: We retrospectively reviewed 122 consecutive patients with acute aortic dissection undergoing arch reconstruction surgery procedure with cardioplegia arrest from January 2017 to December 2019. Patients exclusively received with whole blood cardioplegia (n = 60, January 2017–December 2018) or del Nido cardioplegia (n = 62, January 2018–December 2019). Preoperative and postoperative data were retrospectively reviewed. Results: No significant difference between two groups in mortality (4/60 vs 3/62, p = 0.964), cardiopulmonary bypass time (168.0 ± 10.5 minute vs 165.0 ± 12.5 minute, p = 0.154), aortic cross-clamp time (91.8 ± 9.0 minute vs 93.2 ± 9.5 minute, p = 0.405), selective antegrade cerebral perfusion time (21.8 ± 5.0 minute vs 22.4 ± 4.7 minute, p = 0.496) and postoperative vasoactive inotropic score (34.8 ± 1.9 vs 35.2 ± 2.1, p = 0.272), neurological complications rate (8/60 vs 12/62, p = 0.523), renal insufficiency rate (5/60 vs 7/62, p = 0.807) and the troponin T level (304.8 ± 111.3 vs 315.0 ± 94.9, p = 0.588), respectively. Mean volume of crystalloid was significantly higher in the del Nido group compared to the whole blood cardioplegia group (1010.2 ± 20.3 mL vs 300.0 ± 19.6 mL, p < 0.001). Patients requiring defibrillation was 7/62 vs 28/60 (p < 0.001), with statistical difference in both groups. Conclusion: Short-term outcomes in acute aortic dissection surgery using del Nido cardioplegia solution were acceptable and comparable to conventional multi-dose whole blood cardioplegia. Del Nido cardioplegia technique is associated with lower defibrillations rate and requires a reduced frequency of infusions that results in longer durations between infusions and may be a feasible alternative to conventional whole blood cardioplegia solution in acute aortic dissection surgery.