Introduction: Glaucoma is a leading cause of irreversible blindness worldwide. Lowering intraocular pressure (IOP) is the only strategy documented to delay the appearance and retard the progression of vision loss.Objectives: The present investigation was conducted to evaluate the effect of digoxin (0.00625%), nimodipine (0.5%) and sildenafil (0.3%) on mean intraocular pressure (IOP) of both normotensive and hypertensive eyes in rabbits.Methods: Sixty rabbits were included in the present study . Digoxin, sildenafil and nimodipine ophthalmic solutions were instilled twice daily for 7days in both normotensive and induced hypertensive eyes (that induced by weakly subconjunctival injection of 0.7 ml of betamethasone suspension for 4 weeks). IOP measured by Schiotz tonometer daily at about the same time to avoid IOP diurnal fluctuation. Results: In the present study DW produced no significant change in mean IOP in both normotensive and induced ocular hypertension (P > 0.05). Timolol (0.5%) reduced mean IOP significantly (P = 0.021) by (17.65%) in normotensive eyes and by (20.83%) (P = 0.004) in hypertensive eyes after 1 day of instillation . Mean IOP decreased after one day of treatment by 11.63%, 16.48% and 9.09% in normotensive eyes, on the other hand, mean IOP decreased by 5.59%, 6.2% and 19.29 % in hypertensive eyes when instilled digoxin (0.00625%), nimodipine (0.5%) and sildenafil (0.3%) respectively. A significant results (P ≤ 0.05) were obtained when compared the results of tested drugs with that of DW (as a negative control group),on the other hand there was no significant differences were obtained when compared with that of timolol (0.5%) (as a positive group).Conclusion: The results obtained in this study provide experimental evidences for the effectiveness of digoxin (0.00625%), nimodipine (0.5%) and sildenafil (0.3%) ophthalmic solutions in reducing mean IOP in both normotensive and induced ocular hypertensive eyes in rabbits. In addition to above all tested drugs in their applied doses were found to have tolerable ocular hypotensive effect.