Status epilepticus (SE) is a life-threatening neurologic condition, instigating epileptogenesis to transform normal brain to an epileptic condition. SE is followed by spontaneous recurrent seizures (SRS) and final development of temporal lobe epilepsy (TLE) that is resistant to treatment. Neuroprotective strategies are increasingly put forward as a promising therapy to prevent and/or manage epileptic conditions. In this study, we investigated whether berberis alkaloid, i.e. berberine (BBR), could ameliorate intrahippocampal kainate-induced SE and its consequent epileptogenic process and to explore some underlying mechanisms. BBR was daily administered at doses of 25 or 50mg/kg. Results showed that BBR treatment of kainate-microinjected rats at a dose of 50mg/kg lowered the incidence of SE and SRS. It also significantly restored hippocampal level of reactive oxygen species (ROS), glutathione (GSH), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), activity of catalase and caspase 3, nuclear factor-B (NF-κB), toll-like receptor 4 (TLR4), tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), neural cell adhesion molecule (NCAM), glial fibrillary acidic protein (GFAP), cathepsin D, and heme oxygenase 1 (HO-1). Additionally, BBR protected against hippocampal CA3 neuronal loss and prevented development of aberrant mossy fiber sprouting (MFS) as an essential element of chronic epileptogenic circuit. These data suggest that BBR could mitigate SE and SRS in intrahippocampal kainate model of epilepsy and exert neuroprotective effect and its influence is mainly mediated via suppression of oxidative stress, neuroinflammation, and possibly apoptosis.