Background and Objectives: Myocardial protection during on-pump coronary artery bypass grafting (CABG) limits ischaemic injury, particularly in patients with left main coronary artery disease (LMCAD), in whom severe proximal stenosis may compromise antegrade cardioplegia delivery. We investigated whether combined antegrade–retrograde blood cardioplegia reduces postoperative high-sensitivity cardiac troponin I (hs-cTnI) concentrations, a marker of perioperative myocardial injury. Materials and Methods: We conducted a prospective, single-centre, randomised trial involving 60 adults undergoing elective isolated on-pump CABG for significant LMCAD. Patients were assigned (1:1) to antegrade-only or combined antegrade–retrograde blood cardioplegia. Cardiac biomarkers were measured after induction and at 4, 12, 24, and 48 h after ICU admission. The primary endpoint was peak hs-cTnI within 48 h; key secondary endpoints included the hs-cTnI area under the concentration–time curve, CK-MB, immediate myocardial electrical recovery and 30-day outcomes. Results: All patients received the assigned cardioplegia strategy, with no crossover. Peak hs-cTnI did not differ significantly between the antegrade-only and combined groups (median 529.1 [IQR 829.9] vs. 394.1 [503.4] ng/L; p = 0.21), nor did the hs-cTnI area under the concentration–time curve from 4 to 48 h (12,910.6 [23,127.4] vs. 8112.2 [11,686.2] ng·h/L; p = 0.16). Serial hs-cTnI, CK-MB, total creatine kinase, serum creatinine, immediate myocardial electrical recovery, and 30-day outcomes also did not differ significantly. No deaths, coronary sinus injuries, or other cardioplegia-related complications occurred. Conclusions: In patients undergoing isolated on-pump CABG for significant LMCAD, combined antegrade–retrograde blood cardioplegia did not significantly decrease peak hs-cTnI levels compared to the antegrade-only method. The combined approach was feasible with no cardioplegia-related complications, suggesting that an individualised strategy may be preferable to a routine one. Larger prospective studies are needed to determine whether higher-risk patients may derive greater benefit.