Status epilepticus (SE) is a major neurological disorder and SE survivors often develop acquired epilepsy and cognitive deficits. Thus, it is important to stop SE and limit brain damage. However, rapid pharmacoresistance develops to anticonvulsants as seizure duration lengthens. Recently, acetaminophen was reported to increase endocannabinoid levels by its conversion to AM 404. Further, cannabinoids are potent anticonvulsants. Here we investigated whether acetaminophen would block SE-like activity in hippocampal neurons. Exposure of cultured hippocampal neurons to a low Mg2+ medium elicits high-frequency epileptiform discharges that exceed 3 Hz (in-vitro SE). Acetaminophen (500 μM) blocks the SE-like activity. CB1 receptor antagonist SR 141716A (1 μM) blocked this inhibitory effect of acetaminophen on SE, indicating that acetaminophen was mediating its anticonvulsant effects through CB1 receptors.