There is currently no therapeutic intervention to stem neonatal brain injury after exposure to hypoxia-ischemia (HI). Potential neuroprotective treatments that can be delivered postinsult that target neuroinflammation and are safe to use in neonates are attractive. One candidate is ibuprofen. Ibuprofen is a nonsteroidal anti-inflammatory drug that inhibits cyclooxygenase enzymes and is used in neonates to treat patent ductus arteriosus. We investigated whether ibuprofen can inhibit neuroinflammation and attenuate neuronal damage manifested in a rodent model of preterm HI. Postnatal day 3 (P3) rat pups were subjected to HI (right carotid artery ligation, 30 minutes 6% O₂). Ibuprofen was then administered daily for 1 week (100 mg/kg P3 2 hours after HI, 50 mg/kg P4-P9; subcutaneously). Ibuprofen treatment prevented the P3 HI-induced reductions in brain serotonin levels, serotonin transporter expression, and numbers of serotonergic neurons in the dorsal raphé nuclei on P10. Ibuprofen also significantly attenuated P3 HI-induced increases in brain cyclooxygenase 2 protein expression, interleukin-1β, and tumor necrosis factor levels, as well as the increase in numbers of activated microglia. Thus, ibuprofen administered after an HI insult may be an effective pharmacologic intervention to reduce HI-induced neuronal brain injury in the preterm neonate by limiting the effects of neuroinflammatory mediators.