Pediatric hypoxic-ischemic encephalopathy (HIE) is a condition that occurs when an infant's brain doesn't receive enough oxygen and blood, often leading to brain injury. It typically occurs around the time of birth and can have significant long-term impacts on a child's development and neurological function, affecting up to 8 per 1000 live births, Current diagnostic tools for Pediatric hypoxic-ischemic encephalopathy (HIE) lack both sensitivity and specificity, especially in terms of neuronal specificity. Aims: The current systematic review aims to evaluate Diagnostic markers of pediatric hypoxic encephalopathy for diagnosing term newborns with hypoxic ischemic encephalopathy. Methods: A total of 30 studies were included in this review Following PRISMA guidelines, searches were conducted across PubMed, Web of Science, Science Direct, and Open Grey for English-language studies on biochemical biomarkers, excluding cerebrospinal fluid studies. Studies on Hypoxic-Ischemic Encephalopathy (HIE) were conducted across various global locations, including Egypt, Lebanon, Tokyo (Japan), Santiago de Compostela and Barcelona (Spain), London (England), multiple sites in Italy and Poland, and Dallas, Texas (USA). The majority were prospective, from 2009 to 2020 with one being a retrospective case-control study. Sample sizes ranged from 6 to 108 participants. Results: Key findings highlight serum as the primary fluid for biomarker studies, with proteins such as neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) consistently identified as potential indicators of brain injury severity in HIE. The review emphasizes the necessity for standardized diagnostic criteria and high-throughput screening tools to broaden the spectrum of identifiable biomarkers. NSE and S100B, along with proteins like UCHL-1 and GFAP, emerge as promising candidates for enhancing early diagnosis and treatment outcomes in HIE. Further research into these biomarkers could significantly advance clinical management strategies for affected newborns. Conclusion: The current study concluded that the diagnostic markers enhance nursing diagnoses by providing evidence-based practices to improve patient outcomes and guide the management and care of infants This comprehensive review underscores the significant role of nurses in early intervention, patient monitoring, and family support, ensuring holistic care in pediatric HIE cases. Biomarkers such as neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), UCHL-1, and GFAP have shown promise in diagnosing HIE by correlating with brain injury severity.