The prognosis in neonatal hypoxic ischemic encephalopathy (HIE) depends on early differential diagnosis for justified administration of emergency therapeutic hypothermia. The moment of therapy initiation directly affects the long-term neurological outcome: the earlier the commencement, the better the prognosis. This review analyzes recent advances in systems biology that facilitate early differential diagnosis of HIE as a pivotal complement to clinical indicators. We discuss the possibilities of clinical translation for proteomic, metabolomic and extracellular vesicle patterns characteristic of HIE and correlations with severity and prognosis. Identification and use of selective biomarkers of brain damage in neonates during the first hours of life is hindered by systemic effects of hypoxia. Chromatography– mass spectrometry blood tests allow analyzing hundreds and thousands of metabolites in a small biological sample to identify characteristic signatures of brain damage. Clinical use of advanced analytical techniques will facilitate the accurate and timely diagnosis of HIE for enhanced management.