Transmission of human adenovirus (HAdV) infection and the associated clinical disease can be sporadic or epidemic and manifestations may range from mild infection to severe disease. HAdV has been seen to behave as a proinflammatory virus that can trigger the release of high levels of inflammatory cytokines and chemokines in children. Here, we report an unusual case of an infant with HAdV infection who presented with respiratory illness, with a protracted course, complicated with hyperinflammation and multi-system involvement with clinical characteristics mimicking multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease. The patient was an 11-month-old male infant with a background of infantile epilepsy, epileptic encephalopathy, hemimegaloencephaly, and global developmental delay, diagnosed as Ohtahara syndrome. He was admitted with a three-day history of cough, cold, fever, and respiratory distress. Management was initiated with a heated humidified high-flow nasal cannula and given ceftriaxone and hypertonic saline nebulization. Additionally, he developed loose motion on the fifth day of admission. The reverse transcriptase polymerase chain reaction (RT-PCR) of the nasopharyngeal swab was positive for HAdV. Due to persistent fever, elevated inflammatory markers, multisystem involvement (diarrhea, coagulopathy), an absence of a clear microbial etiology, and an epidemiologic link to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, MIS-C was diagnosed. The first dose of intravenous immunoglobulins (IVIG) was administered over the course of 48 hours and the baby required a second dose of IVIG as the fever failed to settle after the first dose. Within 24 hours of the second IVIG dose, defervescence occurred. His platelet count started to rise, and the baby developed thrombocytosis in the third week of illness. Echocardiography was suggestive of dilatation of mild left main coronary artery. He was weaned off oxygen support by day 14 and discharged on day 17. To our knowledge, this is the first reported case of HAdV infection with hyperinflammatory syndrome and vasculitis akin to MIS-C and Kawasaki disease.