Systemic administration of 3-nitropropionic acid (3-NP), a complex II inhibitor of the electron transport chain, causes motor and cognitive deficits that are associated with excitotoxicity and excessive free radical generation. Recently, cyclooxygenase (COX) inhibitors have been implicated as a neuroprotectant in the treatment of various neurological disorders. The present study was designed to investigate the effects of COX inhibitors in 3-NP-induced cognitive impairment and oxidative stress in rats. Intraperitoneal administration of 3-NP (20 mg/kg for 4 days) showed motor abnormalities and cognitive impairment in rats. Chronic treatment with naproxen (10 and 20 mg/kg) and valdecoxib (5 and 10 mg/kg) once daily for a period of 8 days beginning 4 days prior to 3-NP administration significantly improved 3-NP-induced motor and cognitive impairment in rats. Biochemical analysis revealed that systemic 3-NP administration significantly increased lipid peroxidation and nitrite levels, depleted reduced glutathione levels and reduced succinate dehydrogenase (SDH) activity in the brains of rats, whereas administration of naproxen, a nonselective COX inhibitor (10 and 20 mg/kg p.o.) and valdecoxib, a selective COX-2 inhibitor (5 and 10 mg/kg p.o.) significantly attenuated 3-NP-induced oxidative stress. Cyclooxygenase inhibitors also significantly restored the decreased SDH activity. The results of the present study clearly indicate that naproxen and valdecoxib showed protection against 3-NP-induced motor and cognitive impairment by decreasing oxidative stress.