Background <p>Acute kidney injury (AKI) is a common complication in neonates with hypoxic–ischemic encephalopathy (HIE), however, its diagnosis remains challenging due to the unique physiology of the neonatal kidney. This study aimed to compare commonly used AKI definition systems and to evaluate the clinical relevance of the neonatal RIFLE (nRIFLE) criteria relative to standard creatinine-based definitions in neonates with HIE.</p> Methods <p>Neonates diagnosed with moderate to severe HIE treated with therapeutic hypothermia (TH) were retrospectively evaluated. AKI was defined according to KDIGO and nRIFLE criteria. Agreement between classification systems was assessed, and neonates with and without AKI were compared.</p> Results <p>A total of 82 neonates were included in the study. According to KDIGO definition, AKI was identified in 32 infants (39%). In this group, 1st-&#xa0;and 5th-minute Apgar scores were lower (<i>p</i> = 0.009, <i>p</i> = 0.003, respectively), and lactate levels were higher (<i>p</i> = 0.007). Neonates with AKI had a significantly longer hospital stay (<i>p</i> = 0.007) and a higher requirement for inotropic support (<i>p</i> = 0.002). When patients were evaluated according to the nRIFLE criteria, more infants were classified as having AKI. Neonates identified with AKI according to nRIFLE criteria demonstrated markers of greater clinical severity, including lower Apgar scores (<i>p</i> = 0.024), higher lactate levels (<i>p</i> = 0.03), increased need for inotropic support and blood product transfusions (<i>p</i> = 0.008, <i>p</i> = 0.041, <i>p</i> = 0.001, respectively).</p> Conclusion <p>In neonates with moderate–severe HIE, AKI represents an additional burden of morbidity and remains challenging to diagnose due to neonatal renal physiology. In this high-risk population, nRIFLE criteria may better reflect clinically relevant renal dysfunction beyond standard definitions.</p> Graphical abstract <p></p>