Perinatal tuberculosis (TB) is a rare infectious disease. The diagnosis of perinatal TB is challenging due to its nonspecific clinical manifestations make it difficult to differentiate from other infections, resulting in a high mortality rate of 40-60%. Here we report a 26-day-old neonate with fever, cough, fast breathing, poor feeding, subcostal retraction, bilateral crackles, hepatomegaly, and signs of shock. Clinically, septic shock and pneumonia were suspected. Respiratory distress worsened despite broad-spectrum antibiotics, and kept getting worse up to the point that intubation and assisted mechanical ventilation were needed. The examination of acid-fast bacteria (AFB) stain on the endotracheal aspirate showed a positive result. The patient was diagnosed as having perinatal TB, then treated with anti-TB regimens (isoniazid, rifampicin, pyrazinamide, ethambutol), as well as prednisone and other supportive medical care. Recurrent septic shock, laryngeal edema, and a possibility of ventilator-associated pneumonia (VAP) worsened the patient’s condition. The patient eventually passed away on the 71 st day of care. In conclusion, perinatal TB should be suspected in any neonates with fever, respiratory distress, and hepatosplenomegaly, particularly in those from endemic areas, which fail to respond to broad-spectrum antibiotics. Early diagnosis and treatment are crucial to improve the prognosis of perinatal TB.