To explore the mechanism by which sitagliptin regulates Alzheimer’s disease (AD) through the glycogen synthase kinase-3β (GSK-3β) pathway. Methods: 72 rats were randomly divided into 9 groups. Group I (control): oral drinking water for 8 weeks; Group II (sham operation): on day 1, each lateral ventricle of the rat was infused with 4 μL artificial cerebrospinal fluid; Group III (Aβ1-42): on day 1, each lateral ventricle of the rat brain was infused with 4 μg Aβ1-42; Groups IV, V, VI (Aβ1-42+sitagliptin): on day 1, each hippocampus of the rat was infused with 4 μ g Aβ 1-42, then orally administered different doses of sitagliptin for 8 weeks (the doses of sitagliptin for Groups IV, V, and VI were 1 mg/kg, 2 mg/kg, and 3 mg/kg respectively); Group VII (sitagliptin): orally administered sitagliptin (1 mg/kg) for 8 weeks; Group VIII (Aβ1-42+donepezil): on day 1, each lateral ventricle of the rat was infused with 4 μg Aβ1-42, then orally administered donepezil (1 mg/kg) for 8 weeks; Group IX (donepezil): orally administered donepezil (1 mg/kg) for 8 weeks. After modeling was completed, the memory function of various rats was tested using the Morris water maze. The rats were then sacrificed, and the levels of glucagon-like peptide-1 (GLP-1), soluble Aβ1-42, insulin receptor substrate-1 (IRS-1) (s307), GSK-3 β, acetylcholinesterase (AChE), catalase (CAT), proinflammatory cytokines interleukin-6 (IL-6), IL-1 β, and tumor necrosis factor-α (TNF-α) in the hippocampus of each group were determined; hippocampal HE and Congo red staining were performed for pathological analysis. Results: Water maze test results showed that the platform finding time and swimming distance of rats in the AD model group (Group III) were higher than those in the sham operation group (Group II) (both P<0.001); the levels of hippocampal GLP-1 and CAT were lower than those in the sham operation group (Group II) (P<0.01), and the levels of soluble Aβ1-42, GSK-3β, IL-6, IL-1β, TNF-α were all higher than those in the sham operation group (Group II) (all P<0.01); HE and Congo red staining results showed that the AD model group (Group III) had more cellular infiltration plaque material and typical amyloid protein deposition. The platform finding time and swimming distance of rats in the high-dose (3 mg/kg) sitagliptin AD model group (Group VI) and donepezil AD model group (Group VIII) were lower than those in other model groups (both P<0.001); the levels of rat hippocampal GLP-1 and CAT were higher than those in other model groups (both P<0.05), and the levels of soluble Aβ1-42, GSK-3β, IL-6, IL-1β, TNF-α, IRS-1, and IRS-1(s307) expression, and AChE were all lower than those in other model groups (all P<0.05); the level of GLP-1 in the hippocampus of rats in the high-dose sitagliptin AD model group (Group VI) was higher than that in the donepezil AD model group (Group VIII), and the level of TNF-α was lower than that in the donepezil AD model group (Group VIII); HE and Congo red staining results showed that the infiltration material in the hippocampus of rats in the high-dose sitagliptin AD model group (Group VI) and donepezil AD model group (Group VIII) was reduced compared to the AD model group (Group III), cells were more normal, cytoplasmic acidophilic staining was less, and amyloid protein deposition was reduced. Conclusion: Oral administration of sitagliptin (3 mg/kg) for 8 weeks can improve the memory function of AD rats, reduce brain insulin resistance, alleviate inflammatory response, and reduce AD-like changes in hippocampal neurons, which may be related to the regulation of the GSK-3β signaling pathway.