Rationale: Pertussis is an acute respiratory infection that often occurs in the pediatric population, especially in infants under 3 months old. Bordetella pertussis is the causative agent of pertussis, which can lead to pneumonia, encephalopathy, and pulmonary hypertension, causing death in severe cases. Therefore, an accurate and comprehensive diagnosis of the pathogen is essential for effective treatment. Patient concerns: We report a case of 2-month-old male infant admitted to the pediatric intensive care unit of West China Second University due to hoarse cough for 7 days, accompanied by a crowing-like echo, fever and listlessness, occasional nonprojectile vomiting with anorexia, shortness of breath, accelerated heart rate, cyanosis of the lips, and convulsions. B pertussis was identified by metagenomic next-generation sequencing in blood and cerebrospinal fluid and polymerase chain reaction assay using blood. Diagnoses: The infant was diagnosed with pertussis. Interventions: Intravenous infusion of erythromycin (50 mg/kg/d) for anti-infection and dexamethasone for alleviating intracranial inflammatory reaction were given. Outcomes: The patient was eventually recovered and discharged. Lessons: This case report emphasized the importance of metagenomic next-generation sequencing using cerebrospinal fluid and blood for early diagnosis of pertussis-associated encephalopathy.