The aim of this study is to present the clinical effects and management of Stevens-Johnson Syndrome, which developed during the fourth month of anti-tuberculosis treatment, specifically during the second month of maintenance treatment with Isoniazid and Rifampicin. This case report describes a 50-year-old male patient who developed Stevens-Johnson Syndrome while undergoing tuberculosis treatment. The patient was treated with a combination of Isoniazid and Rifampicin. The clinical features, treatment adjustments, and patient outcomes are detailed. Stevens-Johnson Syndrome developed in the fourth month of treatment, manifesting as widespread bullous erythematous lesions on the hands and feet, covering less than 10% of the body surface area. After discontinuing anti-tuberculosis treatment, the lesions improved within two days. When treatment with Isoniazid and Rifampicin was resumed after a 15-day drug-free period, lesions reappeared within three days, confirming the association of the syndrome with Rifampicin. The treatment regimen was subsequently changed to Moxifloxacin and Ethambutol, resulting in complete resolution of the lesions within two days. Rifampicin-induced Stevens-Johnson Syndrome requires prompt recognition and discontinuation of the causative drug. Healthcare providers, particularly in primary care settings, should be vigilant for cutaneous adverse reactions to anti-tuberculosis medications to ensure timely intervention and management. Further retrospective studies are needed to better understand the incidence and management of these reactions.