BackgroundCurrent diagnostic criteria for hypoxic–ischemic encephalopathy in the early hours lack objective measurement tools. Therefore, this systematic review aims to identify putative molecules that can be used in diagnosis in daily clinical practice (PROSPERO ID: CRD42021272610).Data sourcesSearches were performed in PubMed, Web of Science, and Science Direct databases until November 2020. English original papers analyzing samples from newborns > 36 weeks that met at least two American College of Obstetricians and Gynecologists diagnostic criteria and/or imaging evidence of cerebral damage were included. Bias was assessed by the Newcastle–Ottawa Scale. The search and data extraction were verified by two authors separately.ResultsFrom 373 papers, 30 met the inclusion criteria. Data from samples collected in the first 72 hours were extracted, and increased serum levels of neuron-specific enolase and S100-calcium-binding protein-B were associated with a worse prognosis in newborns that suffered an episode of perinatal asphyxia. In addition, the levels of glial fibrillary acidic protein, ubiquitin carboxyl terminal hydrolase isozyme-L1, glutamic pyruvic transaminase-2, lactate, and glucose were elevated in newborns diagnosed with hypoxic–ischemic encephalopathy. Moreover, pathway analysis revealed insulin-like growth factor signaling and alanine, aspartate and glutamate metabolism to be involved in the early molecular response to insult.ConclusionsNeuron-specific enolase and S100-calcium-binding protein-B are potential biomarkers, since they are correlated with an unfavorable outcome of hypoxic–ischemic encephalopathy newborns. However, more studies are required to determine the sensitivity and specificity of this approach to be validated for clinical practice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12519-023-00698-7.