Temporal lobe epilepsy is the most common form of epilepsy in humans. Caspase activation is a mechanism of cell death induced by seizures. Tellurium (IV) compounds present antitumoral, immunomodulatory and neuroprotective effects due to their ability to inhibit cysteine proteases. We studied the activity of caspase-1, -3 and -8 in the hippocampus of rats exhibiting status epilepticus induced by pilocarpine. All three caspases were activated. Tellurium (IV) compounds RF-07, RF-03 and AS-101 inhibited caspases in vitro, showing high second-order inhibition rate constants. The intraperitoneal injection of RF-07 prior to pilocarpine suppressed the behavioral and electroencephalographic seizure occurrence. According to our results, the caspases are activated as early as 90 min following SE. Tellurium (IV) compounds exerted anticonvulsant effects associated with the inhibition of caspases. These results suggest a promising therapeutic potential of organotellurium (IV) compounds as antiepileptogenic agents.