The ketogenic diet (KD) is an alternative treatment for medically refractory epilepsy. Despite numerous mechanistic hypotheses advanced to explain the anticonvulsant action of the KD, few studies to date have addressed the molecular changes in brain following KD treatment. Here, we present recent experimental results based on systemic administration of kainic acid (KA) in rodents. KA typically induces acute limbic seizures and results in cellular and molecular alterations, accompanied by neuronal death mainly in limbic structures, similar to what has been observed in surgically resected temporal lobe tissue in epileptic patients. We have reported that neuronal degeneration induced by KA is ameliorated by KD treatment via diverse protective mechanisms, including inhibition of caspase-3-mediated apoptosis in hippocampal neurons. Neuroprotective strategies such as the KD, if implemented early, might exert an antiepileptogenic effect, and could prevent associated learning and memory deficits.