Human parechovirus is the most common underrecognised aetiological agent of encephalitis in children younger than 90 days. The aim of this study is to describe the clinical manifestation, laboratory features, and potential risk factors for severe parechovirus-related sepsis-like encephalitis. The case series included five infants aged below three months diagnosed with sepsis-like parechovirus encephalitis. The diagnosis was based on the patients’ neurological symptoms, the criteria of sepsis defined by the National Institute for Health and Care Excellence, and parechovirus-positive cerebrospinal fluid polymerase chain reaction (PCR). The majority of patients presented with irritability, fever, abnormal muscle tone, mottling, decreased activity, tachycardia, abdominal distension, and absence of neonatal developmental reflexes. No abnormalities in the cerebrospinal fluid were identified. Abnormal blood laboratory measurements included lymphopaenia, leukopaenia, and anaemia. The case series highlights the necessity to perform cerebrospinal fluid PCR for parechovirus in infants with sepsis-like illness and neurological signs but without cerebrospinal fluid signs of inflammation.