Tuberculosis (TB) is still a major public health concern in Morocco. Although first-line antituberculosis drugs (ATD) are generally considered safe and effective, serious adverse events can occur. In this case report, we describe a female with pulmonary TB who experienced anaphylaxis induced by rifampicin (RFP) and pyrazinamide (PZA) during ATD therapy. Anaphylactic reactions to first-line ATD can occur and may lead to treatment discontinuation and challenges in finding effective alternative treatment options. Healthcare professionals should be aware of the potential of anaphylaxis with the use of these drugs, especially in patients with a history of lupus. Further research is needed to better understand the mechanisms underlying anaphylaxis and develop effective preventive and management strategies. A young female patient with a history of lupus and splenectomy presented with respiratory symptoms and deterioration of general condition. She was diagnosed with pulmonary tuberculosis and received first-line ATD, which caused complications including liver dysfunction and anaphylactic shock. Despite these challenges, the anaphylactic shock was successfully managed; she was put on a combination of levofloxacin, kanamycin, and ethambutol (ETB), as well as a desensitization protocol for isoniazid (INH); the patient was cured.