There is an upsurge in gestational diabetes mellitus with many devastating consequences for the mother and developing fetus. Insulin therapy remains a mainstay. However, insulin is expensive and comes with the pain of multiple injections. Therefore, there is a need to explore commonly administered oral hypoglycemic agents to cater for the increasing gestational diabetes mellitus-associated neurological complications. This study assesses the effects of glibenclamide, metformin and insulin on the pups’ prefrontal cortex in diabetic pregnant rats. 35 sexually matured adult female rats weighing between 120 g and 160 g were used and assigned into five groups (A to E) of seven rats each group. Diabetes was induced by streptozotocin (45 mg/kg and 35 mg/kg; ip). Hyperglycemic rats were treated with insulin (1.0 UI daily), metformin (200 mg/kg/day) and glibenclamide (0.6 mg/kg/day). Body weight and blood glucose levels were evaluated. Rats were sacrificed at 18-day gestation, the pups were harvested, and their brains were processed for tissue oxidative stress markers and various histological examinations. Glibenclamide and metformin caused a significant blood glucose reduction at 37.9% and 40.7%, respectively, compared to the insulin group (33.09%). There was no significant difference in the body-organ ratio in rats treated with metformin when compared to rats treated with insulin. Metformin and glibenclamide had a significant increase in tissue glutathione reductase and a decrease in malondialdehyde compared with insulin and diabetic control groups. The pups’ prefrontal cortex showed degenerated neuronal cells in the diabetic control animals. The diabetic rats treated with metformin and glibenclamide showed improved pyramidal neurons compared with diabetic and insulin groups. This study suggests that metformin and glibenclamide glycemic control may prevent and improve antioxidant enzymes and reverse some neurotoxic effects caused by streptozotocin-induced diabetes in rats.