Objectives: We aimed to compare the efficacy and adverse events of Bacillus Calmette-Guérin (BCG) versus Mitomycin C (MMC) in high-risk Non-Muscle-Invasive Bladder Cancer (NMIBC) patients. Methods: This randomized controlled study was conducted over 24 months in four hospitals in Egypt. A sample of 90 patients was randomly assigned to either treatment group, with procedures including baseline examinations, a single postoperative instillation of chemotherapy, a 6-week induction cycle of the assigned drug, and regular follow-up cystoscopies and upper urinary tract imaging. Treatment results and side effects were monitored, with data analyzed via Statistical Package for Social Sciences (SPSS). Results: No significant differences were observed in mean age or tumor characteristics ( p > 0.05). However, adverse reactions were significantly higher in the BCG group, including cystitis (40% vs. 17.78%, p = 0.020), hematuria (24.44% vs. 4.44%, p = 0.007), overall local reactions (75.56% vs. 26.67%, p < 0.001), fever (13.33% vs. 2.22%, p = 0.049), and fatigue (17.78% vs. 2.22%, p = 0.014). The MMC group had a slightly higher recurrence rate (28.89% vs. 17.78%, hazard ratio 1.89, 95% CI: 0.78–4.55, p = 0.15) with a shorter median time to recurrence (six vs. 12 months). Progression rates were similar (8.89% MMC vs. 4.44% BCG, p = 0.398). Conclusion: Although BCG and MMC have comparable efficacy in managing high-risk NMIBC, BCG demonstrated a higher rate of adverse reactions. Decision-making should consider this balance, patient preferences, and health status. Further research is needed for the validation and exploration of these findings.