Globally, ischemic stroke is a leading cause of death and adult disability. Previous efforts to repair damaged brain tissue following ischemic events have been hindered by the relative isolation of the central nervous system. We have developed a gelatin nanoparticle-mediated intranasal drug delivery system as an efficient, non-invasive method for delivering 17β-estradiol (E2) specifically to the brain, enhancing neuroprotection, and limiting systemic side effects. Young adult male C57BL/6 J mice subjected to 30 min of middle cerebral artery occlusion (MCAO) were administered intranasal preparations of E2-GNPs, water soluble E2, or saline as control 1 h after reperfusion. Following intranasal administration of 500 ng E2-GNPs, brain E2 content rose by 5.24 fold (P < 0.0001) after 30 min and remained elevated by 2.5 fold at 2 h (P < 0.05). The 100 ng dose of E2-GNPs reduced mean infarct volume by 54.3% (P < 0.05, n = 4) in comparison to saline treated controls, demonstrating our intranasal delivery system's efficacy.