Background The objective of this study was to evaluate the prognostic role of postnatal acute kidney injury (AKI) on neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia (TH). Methods This is a prospective observational study including all neonates with HIE receiving TH between 2009 and 2016 at a single center. AKI was classified according to the Kidney Disease: Improving Global Outcomes definition modified for neonatal age. Child development was assessed using the Griffiths Mental Development Scales (GMDS). Study outcome was defined as unfavorable outcome (including death or disability according to GMDS) or favorable otherwise, at 12 and 24 months. Results One-hundred and one neonates (median gestational age 39 weeks) were included. AKI was diagnosed in 10 neonates (10%). Seven patients died within the first year, 35 patients had disability at 12 months, and 45 patients at 24 months. AKI was associated with increased likelihood of unfavorable outcome at 24 months (100% vs. 59% in neonates without AKI; p  = 0.01). AKI showed good positive predictive value (1.00, 95% CI 0.71–1.00) and specificity (1.00, 95% CI 0.88–1.00), but poor negative predictive value (0.41, 95% CI 0.30–0.52) and sensitivity (0.19, 95% CI 0.11–0.32) at 24 months. Conclusions AKI might be a reliable indicator of death or long-term disability in infants with HIE receiving TH, but the absence of AKI does not guarantee a favorable long-term outcome.