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Objective: Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice results in handling‐induced seizures and is useful for evaluating compounds effective against infection‐induced seizures. However, to date only a few compounds have been evaluated in this model, and a comprehensive study of antiseizure medications (ASMs) has not yet been performed. Furthermore, as the TMEV infection produces marked neuroinflammation, an evaluation of prototype anti‐inflammatory compounds is needed as well. Methods: Male C57Bl/6J mice were inoculated with TMEV (day 0) followed by daily administrations of test compounds (day 3‐7) and subsequent handling sessions (day 3‐7). Doses of ASMs, comprising several mechanistic classes, were selected based on previously published data demonstrating the effect of these compounds in reducing seizures in the 6 Hz model of pharmacoresistant seizures. Doses of anti‐inflammatory compounds, comprising several mechanistic classes, were selected based on published evidence of reduction of inflammation or inflammation‐related endpoints. Results: Several prototype ASMs reduced acute seizures following TMEV infection: lacosamide, phenytoin, ezogabine, phenobarbital, tiagabine, gabapentin, levetiracetam, topiramate, and sodium valproate. Of these, phenobarbital and sodium valproate had the greatest effect (>95% seizure burden reduction). Prototype anti‐inflammatory drugs celecoxib, dexamethasone, and prednisone also moderately reduced seizure burden. Significance: The TMEV model is utilized by the Epilepsy Therapy Screening Program (ETSP) as a tool for evaluation of novel compounds. Compounds reducing seizures in the TMEV comprise distinct mechanistic classes, some with mechanisms of action that extend beyond traditional ASMs. [ABSTRACT FROM AUTHOR]