Three highly utilized strains of mice, common for preclinical genetic studies, were evaluated for seizure susceptibility and behavioral outcomes common to the clinical phenotypes of numerous psychiatric disorders following repeated low-dose treatment with either a gamma-aminobutyric acid (GABA) receptor antagonist (pentylenetetrazole (PTZ)) or a glutamate agonist (kainic acid (KA)). Effects of strain and treatment were evaluated with classic seizure scoring and a tailored behavior battery focused on behavioral domains common in neuropsychiatric research: learning and memory, social behavior, and motor abilities, as well as seizure susceptibility and/or resistance. Seizure response was induced by a single daily treatment of either PTZ (30 mg/kg, intraperitoneally (i.p.)) or KA (5 mg/kg, i.p.) for 10 days. Pentylenetetrazole-treated FVB/NJ and C57BL/6NJ strains of mice showed strong, clear seizure responses. This also resulted in cognitive and social deficits, and increased susceptibility to a high dose of PTZ. Kainic acid-treated FVB/NJ and C57BL/6NJ strains of mice had a robust seizure response, which resulted in hyperactivity. Pentylenetetrazole-treated C57BL/6J mice demonstrated mild hyperactivity, while KA-treated C57BL/6J displayed cognitive deficits and resistance to a high dose of KA but no social deficits. Overall, a uniquely different seizure response profile was detected in the C57BL/6J strain with few observable instances of seizure response despite repeated convulsant administration by two mechanisms. This work illustrated that differing background genetic strains have unique seizure susceptibility profiles and distinct social and cognitive behavior following PTZ and/or KA treatment and that it is, therefore, necessary to consider strain differences before attributing behavioral phenotypes to gene(s) of interest during preclinical evaluations of genetic mouse models, especially when outcome measures are focused on cognitive and/or social behaviors common to the clinical features of numerous neurological disorders.