Introduction:The effects of chronic administration of phenytoin (PHT), levetiracetam (LEV), and PHT + LEV adjunctive treatments were examined on the cognitive functions of male rats. Methods: Twenty-eight male Wistar rats (150-180 g) were randomized into 4 groups (N = 7). Groups I-IV received daily intraperitoneal administration of normal saline (0.2 ml), therapeutic doses of PHT (50 mg/kg), LEV (50 mg/kg) or sub-therapeutic dose of PHT (25 mg/kg) and LEV (25 mg/kg) combination, respectively, for 28 days. Thereafter, the animals were subjected to behavioral assessment and evaluation of the activities of acetylcholinesterase, lipid peroxidation, and lastly the morphological evaluation of the brain. Data were analyzed using descriptive and inferential statistics. The results were presented as mean ± SEM in graphs or tables, while the level of significance was taken at p < 0.05. Results: Working & spatial memory, exploratory activities, and motor-coordination indices were significantly (p = 0.0099) impaired with a reduction in the frontal lobe and hippocampal weight following PHT and PHT + LEV adjunctive treatments. The frontal lobe and hippocampal activities of acetylcholinesterase increased significantly (p = 0.0437) following PHT and PHT + LEV adjunctive treatment. The concentrations of malondialdehyde increased significantly (p = 0.0473) in PHT, LEV, and PHT + LEV compared with the control. There was disorganization in the histoarchitectural profile with chromatolysis, hyalinization, and neural vacuolation in the pre-frontal cortex, hippocampus, and cerebellar tissue, especially in the PHT + LEV treated rats. Conclusion: Impairment of cognitive functions following PHT and PHT + LEV adjunctive treatments may be attributable to the deregulation of cholinergic transmission and neurotoxicity.