The cysteine protease caspase‐3 may be involved in the mechanism of cell death following seizures. Using a rat model of focally evoked limbic epilepsy with continuous electroencephalography monitoring, we investigated seizure‐induced changes in caspase‐3 protein expression and processing, enzyme activity, and the in vivo effect of caspase‐3 inhibition. Seizures were induced by intraamygdaloid injection of kainic acid (0.1 μg) and were terminated after 45 min by diazepam (30 mg/kg) administration. Animals were killed 0‐72 h following diazepam administration. Levels of the 32‐kDa proenzyme form of caspase‐3 were unaffected by seizures. Levels of the 17‐kDa cleaved (active) fragment of caspase‐3 were almost undetectable in control brain, but were increased significantly at 4 and 24 h within ipsilateral hippocampus and cortex in seizure animals. Caspase‐3‐like protease activity was increased within the ipsilateral hippocampus at 8 and 24 h following seizures. Caspase‐3 immunoreactivity was increased within the vulnerable ipsilateral CA3/CA4 subfield at 24 and 72 h following seizures and was associated predominantly, but not exclusively, with neurons exhibiting DNA fragmentation. The putatively selective caspase‐3 inhibitor N‐benzyloxycarbonyl‐Asp(OMe)‐Glu(OMe)‐Val‐Asp(OMe)‐fluoromethyl ketone significantly improved neuronal survival bilaterally within the hippocampal CA3/CA4 subfields following seizures. Collectively, these data suggest that caspase‐3 may play a significant role in the mechanism by which neurons die following seizures.