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Background Custodiol has been used as a multi-organ preservation solution and as cardioplegia in cardiac surgery in several nations, but not elsewhere in the globe. Long procedures can be completed without interruption with just one dosage, which offers myocardial protection for up to three hours. Objective This study compared the effects of Custodiol and Cold Blood Cardioplegia on the protection of the myocardium during minimally invasive cardiac valve surgery. Patients and methods On 82 patients receiving Custodiol and Cold Blood Cardioplegia during Minimally Invasive Cardiac Valve Surgery, a prospective research was done. The investigation took place between January 2021 and March 2022. There were two groups of patients. There were 41 patients in Group (A) who received Custodiol cardioplegia, and there were 41 patients in Group (B) who received cold blood cardioplegia. The study’s secondary endpoint was the measurement of Left ventricular ejection fraction in serial echocardiograms, whereas the study’s primary result was the detection of increased cardiac enzymes in serial measurements, signifying myocardial damage. Results Our data’s statistical analysis revealed that none of the outcomes under investigation exhibited a statistically significant difference between groups. Conclusion As determined by CK-MB and EF, a single-dose of antegrade cold custodiol cardioplegia during minimally invasive cardiac surgery is just as effective at preserving the myocardial as repeated antegrade cold blood cardioplegia.