The ketogenic diet (KD), used successfully to treat a variety of epilepsy syndromes in humans and to attenuate seizures in different animal models, also provides powerful neuroprotection in various CNS injury models. Yet, a direct role for ketone bodies in limiting seizure and neuronal damage remains poorly understood. Using organotypic hippocampal slice cultures, we established an in vitro model of chronic ketosis for parallel studies of its neuroprotective and anti-convulsant effects. Chronic in vitro treatment with a ketone body, D-beta-hydroxybutyrate, protected the cultures against chronic hypoglycemia, oxygen-glucose deprivation, and NMDA-induced excitotoxicity, but failed to suppress intrinsic and induced seizure-like activity, indicating improved neuroprotection is not directly translated into seizure control. However, chronic in vitro ketosis abolished hippocampal network hyperexcitability following a metabolic insult, hypoxia, demonstrating for the first time a direct link between metabolic resistance and better control of excessive, synchronous, abnormal electrical activity. These findings suggest that the KD and, possibly, exogenous ketone administration, can be more beneficial for the treatment of seizures associated with metabolic stress or underlying metabolic abnormalities, and can potentially be used to optimize clinical applications of the traditional KD or its variants.