Haemophilus influenzae (Hi) can colonize in the upper respiratory tract and cause severe pulmonary infections, especially among immunocompromised children. Herein, we report a case of left encapsulated pleural effusion (EPE) due to Hi in a 24-month-old girl with trisomy 21. She was already vaccinated against Hi type b. The Hi biotype II was isolated from both the blood and aspirated sputum obtained upon admission. Ampicillin/sulbactam 180 mg/kg/day was administered intravenously for 34 days with oxygen supplementation for 4 days. She clinically recovered without undergoing thoracic drainage. One month after discharge, the girl developed acute otitis media, and the throat swab was cultured. Nontypeable Hi with the same biotype II was isolated, and the infection was controlled by administering antimicrobials. In this report, a literature review regarding the EPE due to Hi in children is also summarized. Pediatric clinicians should be aware of the possibility of Hi-related EPE because of its rapid progression, although it is rare in clinical settings. In addition, they need to consider the possibility of repetitive respiratory infections with Hi in a child with trisomy 21.