Objective: This study aims to compare del Nido cardioplegia (DNC) and histidine-trypto-phan-ketoglutarate (HTK) cardioplegic solutions in minimally invasive aortic valve replacement (mini-AVR) surgery to discuss the safety level of myocardial protection and rationale for redosing intervals. Methods: During the period from January 2017 to June 2019, 200 patients undergoing mini-AVR (solely or with concomitant procedures) were prospectively randomized to DNC (n = 100) and HTK (n = 100), both up to 90 minutes ischemic time. Patients with ischemic time over 90 minutes, needing a redosing, were further analyzed in 2 subgroups with DNC-R (n = 30) and HTK-R (n = 36). Sensitive biomarkers, in addition to routine biochemistry, were also documented at baseline (T1), after cessation of cardiopulmonary bypass (T2), and on the first postoperative day (T3). Transmural myocardial biopsies were sampled for staining. Results: No statistical differences could be demonstrated in DNC and HTK groups with up to 90 minutes cross-clamp times in routine biochemical measurements and basic perioperative clinical outcomes. DNC-R showed significantly more arrhythmia/AV block incidence resulting in more extended intensive care unit (ICU) stay. Interleukin-6 and syndecan-1 in DNC and DNC-R groups were substantially higher at T2. Aquaporin-4 levels were significantly lower in the DNC-R group, demonstrating unsatisfactory response of cells to an excessive volume at T2. Conclusions: DNC and HTK provided acceptable myocardial protection as single-dose applications. DNC-R had significantly unbalanced levels of biomarkers, and more arrhythmia/AV block incidence resulting in more extended ICU stay. For patients who may need redosing HTK may be preferable to DNC.