Objective: The present study aimed to evaluate and compare the myocardial protection performance between Custodial histidine-tryptophan-ketoglutarate cardioplegic solution and blood cardioplegic solution in the context of totally thoracoscopic cardiac surgery. Methods: A total of 101 patients who underwent thoracoscopic cardiac surgery adopting either blood cardioplegic or histidine-tryptophan-ketoglutarate solution at Guangdong Provincial People’s Hospital from January 2021 to December 2021 were retrospectively enrolled. Postoperative outcomes assessed by myocardial enzyme level, the capacity of return to spontaneous rhythm, left ventricle ejection fraction, myocardial infarction, vasoactive-inotropic score, mechanical ventilation time, intensive care unit stay, hospital stay, mechanical circulatory support, and in-hospital mortality were compared between the two groups. Results: 69 and 32 patients adopted blood cardioplegic and histidine-tryptophan-ketoglutarate solutions, respectively. The cardiac troponin I and creatine kinase-MB at the peak period or at the postoperative period of <24h, 24-48h, and >48h were similar between the two groups (p>0.05). There was also no significance regarding the postoperative left ventricle ejection fraction, vasoactive-inotropic score, and incidence of myocardial infarction (p>0.05). However, blood cardioplegic solution administration resulted in a significantly more occurrence of return to spontaneous rhythm in contrast to the histidine-tryptophan-ketoglutarate solution (p=0.025). Multivariate logistic regression for outcomes revealed that histidine-tryptophan-ketoglutarate administration was associated with a lower possibility to return to spontaneous rhythm (odds ratio (OR)=0.238; confidence interval CI=0.072-0.783; p=0.018]. Additionally, increased aortic cross-clamp time per 10 mins was associated with a higher risk of myocardial infarction (OR=1.499; CI=1.161-1.934; p=0.002) while increased total volume was associated with a lower risk of myocardial infarction (OR=0.997; CI=0.994-0.999; p=0.029) Conclusion: Delivery of histidine-tryptophan-ketoglutarate solution offered equivalent myocardial protection to the delivery of blood cardioplegic solution in patients undergoing totally thoracoscopic cardiac surgery. In this setting, the histidine-tryptophan-ketoglutarate seems to be associated with decreased incidence of postoperative return to spontaneous rhythm.