Renal ischemia/reperfusion (I/R) injury is a common pathological condition. Studies reported renal toxicity following administration of triptans which are commonly used for treating migraine headaches. In order to investigate the effects of sumatriptan and the molecular mechanisms involved in renal I/R injury in rats, ischemia was induced by bilateral clamping of renal pedicles followed by 24-hour reperfusion. Sumatriptan was administered in 3 different doses (5, 10, 20 mg/kg) before I/R injury induction. Biochemical and histopathological changes were evaluated. The contribution of nitric oxide in modulating the effects of sumatriptan was determined by administrating aminoguanidine at 50 m/kg 60 min before I/R injury. The tissue level of nitrite, Superoxide dismutase (SOD) and Malondialdehyde (MDA) were measured. Sumatriptan at 10 and 20 mg/kg increased the serum level of Cr and BUN significantly. There was also a significant increase in nitrite level of animals that received 10 mg/kg of sumatriptan. Co-administration of sumatriptan with aminoguanidine significantly decreased the BUN and Cr. Depletion of SOD level (p<0.05) and elevation of serum levels of MDA (p<0.001), indicated the involvement of oxidative stress in sumatriptan adverse effects. Overall, the administration of sumatriptan intensified renal I/R injury through activation of iNOS and oxidative responses in rats.