Chronic epilepsy can begin with isolated early-life prolonged seizures followed by remission and the re-emergence of seizures later in life. Seizures are known to trigger a neuroinflammatory response to promote neuronal damage and increase the risk of epilepsy. We examined whether post-seizure anti-inflammatory treatment with dexamethasone after early-life seizures could decrease future seizure susceptibility and ameliorate heightened microglia activation and cell injury in response to later-life seizures. Using a "two-hit" model, early-life seizures (SZ) were induced in rats on postnatal day (P) 25 by systemic kainic acid (KA) injection followed by later-life KA at P39. P25 animals were administered anti-inflammatory drugs for 2 or 7 days after first KA exposure to inhibit seizure-induced inflammation. Hippocampal microglial activation was measured after first or second KA treatments to assay neuroinflammation, and the latency and severity of seizures to the second KA treatment were measured to determine seizure susceptibility. In situ end labeling for DNA fragmentation was used to compare KA-induced neuronal injury between treatment groups after the second KA administration. KA-SZ at P25 caused marked microglia activation within 48 hours. At P39, KA-SZ in rats without prior seizures caused a modest (2-fold) increase in microglia assayed 72 hours after KA. In contrast, microglia were markedly activated (5-fold) in response to a second KA-SZ at P39. Short-course (2 days) dexamethasone significantly decreased seizure-induced microglia activation at P25, and ameliorated the exaggerated microglia activation, cell injury, and heightened susceptibility to second-hit seizures. Although short-course dexamethasone was effective, longer term (7 days) administration of dexamethasone resulted in decreased weight gain and increased mortality in animals with or without KA-induced seizures. These data indicated that acute short-term steroid therapy after SZ could inhibit seizure-induced microglia activation and decrease the long-term damaging effects of early-life SZ. These results further implicate seizure-induced inflammation and activation of innate immunity mediated by microglia in the pathogenesis of childhood epilepsy.