Background: Oxidative stress and systemic inflammation during cardiac surgery can lead to postoperative complications. Although vitamin C and thiamine (vitamin B1) have individually demonstrated protective effects, their combined effects remain underexplored. This study aimed to evaluate the efficacy of combined vitamin C and B1 therapy versus that of vitamin C alone in reducing inflammatory and cardiac biomarkers and improving postoperative outcomes in patients undergoing cardiac surgery. Methods: In this prospective, double-blind, randomized controlled trial, 64 patients scheduled for elective cardiac surgery at a tertiary care center were randomized to receive either 1000 mg vitamin C or a combination of 1000 mg vitamin C and 100 mg vitamin B1 at four perioperative time points. Primary outcomes included changes in inflammatory biomarkers [C-reactive protein, interleukin-6 (IL-6), and white blood cells], and cardiac biomarkers [creatine kinase-MB, Troponin-I, and lactate dehydrogenase]. Secondary outcomes included hemodynamic parameters and left ventricular function. Results: Compared with vitamin C alone, combined vitamin B1 and vitamin C significantly reduced postoperative cardiac biomarker levels. IL-6 levels were significantly lower immediately in the combined group; however, this effect was not sustained at 24 h post-surgery. Up to 24 h after surgery, no significant differences in hemodynamic stability or left ventricular ejection were observed between the groups. Notably, the combined therapy group demonstrated a lower incidence of postoperative arrhythmias and shorter dobutamine duration within 24 postoperatively. Conclusions: Combined vitamin C and B1 therapy significantly reduced markers of myocardial injury and early inflammatory responses (IL-6) in patients undergoing cardiac surgery, suggesting its potential as a protective agent.