Epilepsy is a neurological disorder that affects over 65 million people globally. The initial identification of antiseizure efficacy and tolerability of any investigational agent is routinely defined in mouse and rat models of epilepsy. C57BL/6 mice are a commonly used inbred strain for antiseizure drug discovery, while CF-1 mice are a commonly used outbred strain. Although there is established data on the median effective anticonvulsant doses (ED50) of common prototype antiseizure drugs (ASD) in mice, there is limited quantitative data pertaining to the acute impact of anticonvulsant doses of ASDs on locomotor activity in an open field, which may inform on the potential for adverse effects in a clinical setting. This study aimed to provide a quantitative evaluation of the impact of ASDs on locomotor behavior to provide an added way to compare investigational agents to ASD standards-of-care. Male C57BL/6 or CF-1 mice (n = 8/treatment group/strain) were habituated to an open field 24 hours prior to the testing day. On the day of testing, mice were administered prototype ASDs (valproic acid, carbamazepine, levetiracetam, lamotrigine, phenobarbital, diazepam, ethosuximide, phenytoin, gabapentin) or vehicle by the intraperitoneal route. Mice were then allowed to explore the open field for the 30 minute period encompassing the time of peak effect of each ASD. Endpoints of locomotor behavior in the open field included time spent in the center of the field, vertical rearing, fecal boli, and total distance traveled. In CF-1 mice, diazepam generally reduced all measures of exploratory behavior whereas gabapentin increased the total distance traveled. This study establishes a comparative pharmacological profile of the effect of prototype ASDs on exploratory locomotor behavior of male outbred CF-1 and inbred C57BL/6 mice.