Abstract: Insulin resistance is a hallmark of type 2 diabetes (T2DM) and can increase the risk of cognitive impairment, including Alzheimer’s disease. Nuciferine, an alkaloid from lotus leaves, shows neuroprotective effects. This study investigated nuciferine’s protective role in T2DM-induced cognitive impairment (T2DM-CI) and its mechanisms. Mouse models were created using high-fat diets and streptozotocin, along with high glucose-induced HT-22 cells. Nuciferine reduced blood glucose, improved cognitive function, and mitigated glial cell activation, neuron and synapse loss in T2DM mice. It enhanced insulin signaling by increasing protein levels of IR, IRS1, and IGF-1R, reversing PI3K and AKT phosphorylation, inhibiting GSK3β activity, and reducing hyperphosphorylated Tau in HT-22 cells and T2DM mice. mRNA levels of these molecules matched their protein levels. Further studies revealed that nuciferine directly interacts with IR, knocking out IR abolished its effects on the PI3K/AKT pathway. Thus, nuciferine activates the PI3K/AKT pathway via IR, improving insulin resistance and slowing T2DM-CI progression.