Inflammatory processes play a critical role in the pathogenesis of the neurodegenerative disorders and are associated with cognitive impairments. Nonsteroidal anti-inflammatory drugs (NSAIDs) and nitric oxide releasing NSAIDs are reported to be effective in reducing the risk of developing AD or cognitive impairments. Present experiments were performed to study the possible effect of nitro naproxen (NO-naproxen) on cognitive performance of young, aged and lipopolysaccharide (LPS) treated mice (an animal model of AD) using one trial step–through type of passive avoidance and in elevated plus maze task. Chronic administration (15 days) of naproxen (ED50 dose) and NO-naproxen (molar equivalent of naproxen) significantly reversed the age-induced retention deficits in both test paradigms but the effect of NO-naproxen was pronounced as compared to naproxen. In young and LPS- treated mice, chronic administration of NO-naproxen produced a significant increase in cognitive performance as compared to naproxen. Further, NO-naproxen did not produce any alteration in gastric function since naproxen was associated with gastric toxicity (ulcer index, pH and free/ total acidity). Based on this the study indicates that chronic treatment with nitric oxide releasing NSAIDs reverses the cognitive deficits in age- and LPS treated mice. These findings indicate that NO-NSAIDs besides inhibiting the caspase activity and pro-inflammatory cytokines in CNS are less toxic to the gastrointestinal tract and may prove to be suitable for the treatment of AD.