Background <p>Primary amoebic meningoencephalitis (PAM), caused by Naegleria fowleri, is a rare but often fatal central nervous system infection that mimics bacterial meningitis. This similarity can lead to misdiagnosis and delayed treatment, especially in neonates and infants, resulting in poor outcomes. This study evaluates the clinical and paraclinical features, diagnostic challenges, treatment strategies, and outcomes of PAM in this vulnerable population, emphasizing the importance of early and accurate diagnosis and treatment.</p> Methods <p>This systematic review followed the PRISMA statement. A comprehensive literature search was conducted in PubMed, Web of Science, Scopus, ScienceDirect, and Google Scholar to identify studies without language restrictions describing PAM in neonates and infants published up to December 2025.</p> Results <p>Thirteen studies reporting 13 patients (2 neonates and 11 infants, aged 11 days to 12 months) were included. Fever was found in all patients. Other prevalent manifestations were seizure, decreased level of consciousness, and vomiting. Exposure histories were heterogeneous and often involved contaminated well water and other freshwater sources. Cerebrospinal fluid (CSF) analysis consistently demonstrated neutrophilic pleocytosis, elevated protein levels, and reduced glucose concentrations. Neuroimaging findings varied, with survivors commonly exhibiting limited abnormalities such as hydrocephalus or focal lesions. Microbiologic confirmation was primarily done by CSF microscopy, followed by CSF culture and CSF polymerase chain reaction. Amphotericin B–based combination therapy was the most frequently employed treatment; however, outcomes remained variable, with a high overall mortality rate.</p> Conclusions <p>PAM in neonates and infants presents substantial diagnostic and therapeutic challenges due to nonspecific clinical manifestations, often unclear or atypical exposure histories, and rapid disease progression. The clinical presentation frequently resembles acute bacterial meningitis, which may lead to empiric antibacterial therapy and delays in initiating appropriate anti-amoebic treatment. Early clinical suspicion, timely use of microbiological diagnostic methods, and prompt initiation of targeted therapy may be associated with improved survival. Preventive measures, emphasizing the use of safe household water, are important, especially preventing neonates and infants from being exposed to untreated environmental water sources such as well water. Considering the high mortality rate, enhancing early diagnostic methods and optimizing therapeutic interventions remain essential to improving outcomes in these patients.</p>