Objective: To evaluate the impact of vitamin D supplementation on TB recurrence rates, immune response, and overall health outcomes in individuals at high risk for tuberculosis relapse. Methodology: This study aimed to investigate the efficacy of vitamin D supplementation in reducing tuberculosis (TB) recurrence in high-risk populations. This study was conducted in 23 public schools with a high TB burden, the study was a multicentre, phase III, double-masked, randomized, placebo-controlled trial. Children aged 6-11 years, with no history of TB infection, chronic illnesses, or vitamin D supplementation exceeding 400 IU/day, were enrolled. Participants were randomly assigned to receive either a weekly dose of 350 µg of vitamin D3 or a placebo. Over a 36-month period, clinical outcomes, immune responses, and adverse events were monitored. Data analysis utilized mixed-effects logistic and linear regression models to assess the impact of vitamin D supplementation on TB recurrence, immune response, and safety outcomes. Results: The baseline characteristics of the study participants were comparable between the vitamin D and placebo groups. The primary outcome, assessed through the QuantiFERON-TB Gold (QFT-Plus) test, revealed no significant difference between the groups, with 11.4% of the vitamin D group and 13.0% of the placebo group testing positive at the 0.35 IU/ml threshold (adjusted odds ratio 0.86, p = 0.35). No significant differences were observed in the secondary outcome, with 3.7% of the vitamin D group and 2.8% of the placebo group testing positive at the 4.0 IU/ml threshold. Serum 25(OH)D3 concentrations were significantly higher in the vitamin D group at all follow-up intervals, with a peak difference of 44.7 nmol/L at 24 months. No serious adverse events related to vitamin D supplementation were reported. The incidence of active TB was 0.0% in the vitamin D group and 0.4% in the placebo group. Conclusion: Vitamin D supplementation did not significantly reduce TB recurrence or improve immune response in this high-risk population. Although vitamin D supplementation successfully increased serum 25(OH)D3 concentrations, it did not show a meaningful impact on TB infection markers or active TB incidence. These findings are consistent with other studies that have explored the potential role of vitamin D in TB prevention, where mixed results have been observed. Future research should explore different dosages, durations, and study populations to further understand the role of vitamin D in TB prevention and recurrence.