Diabetes is a long-standing disease that leads to secondary complications of capillaries such as retinopathy, nephropathy and neuropathy.  Emerging evidence suggests that diabetes may also affect the cerebromicrovasculature, the blood-brain barrier (BBB), and lead to changes in the brain that affect cognition and mood.  Therefore, it is important to identify natural compounds that may have therapeutic benefit for reducing BBB dysfunction and improve patient quality of life.  Preclinical evidence suggests that sesamol, a natural antioxidant in sesame seed oil, could have therapeutic benefit for treating BBB dysfunction during diabetes.  Similarly, paroxetine, which shares a methylenedioxy moiety with sesamol shows clinical benefit for treating neuropathic pain associated with diabetes.  This review emphasizes BBB dysfunction as a treatable secondary complication associated with diabetes and examines the evidence for the use of natural compounds like sesamol or existing therapies like paroxetine to help restore BBB function.