Inter-individual pharmacokinetic variability significantly impacts drug levels, making standard weight-based dosing (WBD) of anti-tuberculosis drugs prone to subtherapeutic or toxic concentrations, which may lead to resistance or adverse effects. This study evaluates the role of Therapeutic Drug Monitoring (TDM)-guided therapy versus standard WBD in managing spinal tuberculosis. The study included 56 patients (22 TDM, 34 non-TDM). In the TDM group, serum drug levels of isoniazid and rifampicin were tested two weeks after starting standard WBD. Doses were then adjusted to achieve therapeutic thresholds, rechecked after one week, and subsequently monitored. Outcomes were classified as favorable or unfavorable. Functional outcomes were measured using the Oswestry Disability Index (ODI) and visual analogue scale, while radiological outcomes were assessed by MRI/radiographs. All patients were followed for two years post-treatment. At baseline, 36.3% of TDM patients had subtherapeutic isoniazid levels and 54.5% had subtherapeutic rifampicin levels. Both cohorts had no significant difference in their end-of-treatment outcomes, despite the TDM group having a higher disease burden and comorbidity. No relapses were noted in either group at 24 months. Approximately 77.2% of patients underwent dose adjustment for isoniazid and rifampicin levels that were frequently subtherapeutic in the TDM group. The non-TDM group exhibited three patients with hepatotoxicity while there were none in the TDM group. Two patients who had unfavorable outcomes in the non-TDM group were eventually managed with TDM-adjusted dosing, which led to a good response to treatment. TDM may prove to be a useful adjunct to WBD, especially in complex spinal tuberculosis cases with multiple comorbidities. Its application in such scenarios needs further exploration.