Triptolide is an epoxidized diterpene lactone isolated from Tripterygium wilfordii. Studies have shown that triptolide exerts organ-protective effects. However, it remains unknown whether triptolide improves Alzheimer's disease (AD)-like presentations.Thirty healthy 8-week-old male C57BL/6J mice were randomly divided into control (n = 10), model (n = 10), and triptolide (n = 10) groups. Amyloid-β (Aβ)42 was injected bilaterally into the ventricles of mice in the model group. Triptolide was injected intraperitoneally daily after injecting Aβ42 (a total of 30 days) in the triptolide group.Learning and memory were tested using the Morris water maze test. The deposition of Aβ42 in the hippocampus was detected using immunohistochemical staining.In the hippocampus, three synaptic-associated proteins-gephyrin, collybistin, and GABRA 1 -were detected by western blotting. Furthermore, we used ELISA to detect proinflammatory cytokines, including TNF-α and IL-1β, in the blood and hippocampus. Moreover, superoxide dismutase (SOD), malondialdehyde (MDA), and GSH levels were measured using the corresponding kits. We found that triptolide improved spatial learning and memory in AD-like mice. Additionally, triptolide maintained the expression of gephyrin, collybistin, and GABRA 1 and reduced Aβ in these mice. Additionally, triptolide reduced the expression of inflammatory cytokines and decreased oxidative damage in AD-like mice. Our study suggests that triptolide attenuates AD-like changes in the mouse brain.