Current anti-epileptic drugs remain to be unsatisfactory, new therapeutic approaches are needed. Circular RNA is a promising class of therapeutic RNAs. Recent studies have shown the role of circRNA in the pathologic process of epilepsy. In this study, we identified the circRNA in epileptic patients in remission that inhibited the epileptic course. By comparing the profiles of differentially expressed circRNAs in peripheral serum between patients in remission and those not in remission, we found that the level of hsa_circ_0000288 (circ288) was markedly elevated in the epileptic patients in remission. We established a kainic acid-induced status epilepticus model in mice. Overexpression of Circ288 by injecting adeno-associated virus (AAV)-circ288-overexpression vector into hippocampi significantly ameliorated epilepsy-induced neuronal injury, promoted hippocampus neurogenesis, and inhibited abnormal migration of newborn neurons into the dentate hilus. Moreover, circ288 overexpression significantly decreased the epileptiform discharges and the spontaneous seizures in the chronic phase of epileptogenesis and alleviated mood disorders (anxiety, depression), and cognitive deficits in epileptic mice. We revealed that circ288 directly bound to an RNA-binding protein caprin1 and inhibited its degradation. The protective action of circ288 was reversed by the knockdown of caprin1 in an in vitro epileptic model and lost in the neuron-specific caprin1 knockout mice (CaMK2α-Cre:Caprin1