Diabetes is associated with increased blood brain barrier (BBB) permeability resulting in neurological deficits. The present study investigated the role of S-nitrosoglutathione (GSNO) on tight junction proteins and cell adhesion molecules in streptozotocin-induced diabetic mice. Diabetes was induced by intraperitoneal injection of streptozotocin (40 mg/kg body weight) for 5 days in mice. GSNO was administered daily (100 μg/kg body weight, orally) for 8 weeks after the induction of diabetes. A significant decline was observed in the cognitive ability of diabetic animals assessed using radial arm maze test. A significant increase was observed in nitrotyrosine levels in cortex and hippocampus of diabetic mice. Relative mRNA and protein expression of tight junction proteins viz; zona occludens-1 (ZO-1) and occludin were significantly lower in the microvessels isolated from cortex and hippocampus of diabetic animals, whereas expression of claudin-5 was unaltered. Immunofluorescence of tight junction proteins confirmed loss of ZO-1 and occludin in the diabetic brain. Furthermore, significant increase in interstitial cell adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 mRNA and protein levels was observed in diabetic animals. Ultrastructure of microvessels from diabetic brain was also altered thereby confirming BBB disruption. GSNO administration to diabetic animals, on the other hand, was able to ameliorate loss of ZO-1 and occludin as well as normalize ICAM-1 and VCAM-1 expression, restore BBB integrity, and improve cognitive deficits. The findings clearly suggest that GSNO is a therapeutic molecule with potential to protect BBB and prevent diabetes induced neurological deficits.