The aim of the study was to assess acute kidney injury (AKI) and its contributing risk factors among neonates to reduce morbidity and mortality. The study included 310 neonates who were admitted to the neonatal intensive care unit (NICU). Serum creatinine (SCr) was elevated at admission, after 48 h, and before discharge or death. AKI was defined by either an acute rise in SCr of at least 0.3 mg/dL within 48 h or an increasing or persistently high level of SCr >1.5 mg/dL after 48–72 h of life. The patients who developed AKI were studied regarding the most common risk factors and outcomes. The prevalence of AKI in these neonates was 11.9%. Nephrotoxic drugs were the highest risk factor among patients with AKI, but this was not statistically significant different from patients without AKI. Perinatal asphyxia (59.5%), respiratory distress syndrome (48.6%), shock (43.2%), prematurity (40.5%), and sepsis (37.8%) were the main risk factors of AKI following the nephrotoxic drugs (64.9%). The mortality rate for cases with AKI was 62.1%, with a statistically significant difference from non-AKI neonates. The death rate was higher among neonates born before 36 weeks' gestation. There was no statistical difference between oliguric and non-oliguric neonates with AKI regarding the outcome. The overall incidence of AKI in sick neonates admitted to the NICU was 11.9%. Nephrotoxic drugs, perinatal asphyxia, shock, and prematurity were the main risk factors for developing AKI.