Drug-drug interaction is an important issue for the development of safe pharmaceutical drugs. Propranolol is a non-selective, competitive antagonist at beta-adrenergic receptors. Propranolol is used to control hypertension, pheochromocytoma, myocardial infarction, cardiac arrhythmias, angina pectoris and hypertrophic cardiomyopathy. Also, it is used to control symptoms of sympathetic overactivity in the management of hyperthyroidism, anxiety disorders and tremor. Phenytoin is a voltage-gated sodium channel blocker; it is a major anti-convulsant drug that is very effective in controlling a wide variety of seizure disorders. In this study, the elevated plus maze test was applied using five groups of male Albino mice, where each group consisting of six mice. The first group is control and given 1.0% tween 80 with a dose of 5.0 ml/kg, the second group received propranolol 10 mg/kg, the third group received phenytoin 20 mg/kg, the fourth group received a combination of propranolol and phenytoin and the fifth group received diazepam (1.0 mg/kg) as a standard. It was found that propranolol alone produces anti-anxiety effect which is abolished when administered with phenytoin. Thus, the combined treatment of propranolol and phenytoin showed no significant difference compared to phenytoin alone or propranolol alone. It can be concluded that propranolol has an anti-anxiety-like effect phenytoin antagonizes the propranolol anxiolytic effect when administered together. Propranolol, phenytoin and the combination of both decrease the spontaneous motor activity of mice. Propranolol and phenytoin partially antagonize each other in spontaneous motor activity.