The current investigation aimed to determine the effects of pre-treatment of acetaminophen on seizure susceptibility and expressions of hippocampal oxidative-nitrosative stress and inflammatory markers after exposure to pentylenetetrazole administration in a mouse model. The seizure symptoms of pentylenetetrazole-treated mice were assessed using Racine classification and latency to first myoclonic jerk. Then, several parameters including TAS, TOS, NO, TNF-α, caspase-3, GABA, and glutamate levels were quantitated by commercial kits. The pre-treatment of acetaminophen significantly suppressed pentylenetetrazol-induced seizures. Also, it significantly increased the TAS and GABA values and significantly decreased the TOS, NO, TNF-α, caspase-3, and glutamate values in the hippocampus. These findings are indicative of the antiseizure potential of pre-treatment with acetaminophen in the pentylenetetrazole-induced acute seizure model of epilepsy. This effect may be due to its impact on antioxidant, anti-inflammatory, and anti-apoptotic pathways.