Oxidative stress and inflammatory damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. The present study examined the hypothesis that intranasal delivery of nanoformulation of curcuminoids would reduce oxidative stress-associated brain injury after middle cerebral artery occlusion (MCAO). The rats were subjected to 2 h of MCAO followed by 22 h reperfusion, after which the grip strength, locomotor activity was performed. The effects of treatment in the rats were assessed by grip strength, locomotor activity and biochemical studies (glutathione peroxidase, glutathione reductase, lipid peroxidation, superoxide dismutase, and catalase) in the brain. Pretreatment with polymeric N-isopropyl acryl amide (PNIPAM) nanoparticles formulation of all three curcuminoids (curcumin (Cur), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC)) at doses (100 μg/kg body weight) given intranasally was effective in bringing significant changes on all the parameters. While nanoformulation of curcumin at a dose of 100 μg/kg body weight was most active in the treatment of cerebral ischemia as compared to others nanoformulation of curcuminoids. The potency of antioxidant activity significantly decreased in the order of PNIPAM nanoformulation of Cur > DMC >> BDMC, thus suggesting the critical role of methoxy groups on the phenyl ring.