Background and objectives Insulin resistance of the brain is a specific form of type2-diabetes mellitus (T2DM) and the active insulin-signaling pathway plays a neuroprotective role against damaging conditions and Alzheimer's progression. The present study identifies the mediated emerging effects of the Nigella sativa oil (NSO) on the memory enhancing process, its anti-oxidative, acetylcho-linestrase (AChE) inhibition, anti-brain insulin resistance and anti-amyloidogenic activities. In addition, the possible role of some anti-diabetic drugs in the neuro-protection processes and their effect in combination with NSO and/or the insulin receptor inhibitor IOMe-AG538 were investigated. Methods T2DM-induced rats were orally and daily administrated 2.0 ml NSO, 100 mg metformin (MT), 0.8 mg glimepiride (GI) and different combinations (100 mg MT & 2.0 ml NSO, 0.8 mg GI & 2.0 ml NSO and 2.0 ml NSO & intraperitoneal injection of 1/100 LD50 of IOMe-AG538) per kg body weight for 21 days. Results A significant increase in the brain lipid peroxidation and decrease in the antioxidant status with peripheral and central production of pro-inflammatory mediators were observed in diabetes- induced rats. The brain AChE was activated and associated with diminished brain glucose level and cholinergic function. In addition, the brain insulin resistance and the attenuated insulin signaling pathway (p-IRS/p-AKT/p-GSK-3 beta) were accompanied by an augmentation in GSK-3 beta level, which in turn may contribute in the extensive alterations of Tau phosphorylation along with changes in PP2A level. Furthermore, neuronal loss and elevation in A beta-42 plaque formation were observed due to a low IDE formation and an increased expression of p53, BACE1 and APP with diminished ADAM10, SIRT1 and BDNF levels. The expression profile of AD-related miRNAs in sera and brain tissues displayed its neuro-protection role. The treatment of diabetes-induced rats with NSO and the anti-diabetic drugs alone and/or in combination have the potential to suppress the oxidative stress, the pro-inflammatory mediators and amyloidogenic pathway. Moreover, it lowers the insulin receptor inhibitory effect of IOMe-AG538 and modifies the insulin-signaling pathway. Therefore, it prevents the neurotoxicity, amyloid plaque formation and Tau hyper-phosphorylation and restores AD-related miRNA normal levels. Conclusion These data suggest that NSO or its combined treatments with anti-diabetic drugs have a possible benefit as disease modifying agents for the insulin resistance in the brain through enhancing brain insulin signaling pathway.