Introduction: del Nido cardioplegia is a newer solution getting popular worldwide, whereas in Nepal, St. Thomas cardioplegia solution is conventionally used. There is no national recommendation on cardioplegia solutions supported by evidences from Nepalese studies. This study aimed to evaluate and compare the efficacy of these solutions in Nepalese patients undergoing coronary artery bypass grafting. Methods: Patients undergoing coronary revascularization, from May 2018 to December 2019, were randomized into St. Thomas and del Nido groups based on the cardioplegia administered, with 45 patients in each group. Preoperative, intraoperative, and postoperative parameters and cost of cardioplegia preparation in the two groups were compared. Results: The cardiopulmonary bypass time (106.13 ± 24.65 minutes vs 107.62 ± 18.69 minutes, p = 0.02), aortic cross clamp time (66.22 ± 15.40 minutes vs 72.07 ± 12.23 minutes, p = 0.04), volume (1059.22 ± 100.30 ml vs 1526.67 ± 271.81 ml, p < 0.001) and number of cardioplegia doses (1.00 ± 0.00 vs 2.51 ± 0.66, p < 0.001) were significantly lower with del Nido cardioplegia. A lower CPK-MB at second post-operative (59.91 ± 31.62 vs 73.82 ± 37.25, p = 0.03) and a higher left ventricle ejection fraction at discharge (56.33 ± 8.94% vs 50.45 ± 8.55%, p < 0.001) was observed in del Nido group. There was one death in St. Thomas group. ICU and hospital stay were similar in both groups. St. Thomas solution was found to be costlier than del Nido solution (USD 5.40 ± 0.96 vs USD 3.50 ± 0.34, p < 0.001). Conclusion: The del Nido cardioplegia was found to be efficacious, safe and more economical alternative to St. Thomas solution.