Objective To characterize the neuroprotective effect of tanshinone IIA (Tan IIA) and its effects on the phosphatidylinositol-3-kinase / protein kinase B (PI3K/ AKT) pathway in a mouse model of Alzheimer’s disease (AD). Methods A mouse model of AD was prepared by the lateral intracerebroventricular injection of lipopolysaccharide (LPS). Mice with AD were randomly allocated to a model group, and low-dose, medium-dose, and high-dose Tan IIA groups, and untreated mice were used as a control group. Tan IIA treatment groups were administered Tan IIA intraperitoneally at 1, 5, or 10 mg / kg, once daily for 7 d. The learning and memory of the mice in each group were assessed using the Morris water maze, Y-maze, and autonomous activity tests. Pathological changes in the brain were assessed using hematoxylin and eosin- stained sections. The concentrations of brain-derived neurotrophic factor (BDNF) and cholinergic and inflammatory factors in brain tissue homogenates were measured by ELISA. The expression of ionized calcium binding adaptor molecule-1 (IBA- 1) and glial fibrillary acidic protein (GFAP) in brain tissues were assessed using immunohistochemistry. The expression of nuclear factor κB (NF-κB), toll-like receptor 4 ( TLR4), PI3K, and AKT was measured by Western Blot. Results There were higher AchE, IL-6, and TNF-α, IBA-1, GFAP, p-NF-κB/ NF-κB and TLR4 concentrations in the brain tissue and escape latency in the model group than in the control group (P<0. 05); whereas the free alternation, and BDNF, Ach, p-PI3K/ PI3K, and p-AKT/ AKT concentrations were significantly lower ( P< 0. 05 ). The escape latency and the concentrations of AchE, IL-6, TNF-α, IBA-1, GFAP, p-NF-κB/ NF-κB, and TLR4 in brain tissue were significantly lower in the Tan IIA treatment groups than in the control group (P<0. 05), whereas the free alternation and BDNF, Ach, p- PI3K/ PI3K, and p-AKT/ AKT concentrations in brain tissue were significantly higher (P< 0. 05). The effects of the high dose of Tan IIA were the most marked. However, there were no significant differences in the autonomous activity distances among the groups (P> 0. 05). Conclusions Tan IIA protects mice with AD from nerve damage, improves their learning and memory, which may be achieved via activation of the PI3K/ AKT pathway and a reduction in brain inflammation, which would inhibit the excessive activation of microglia and astrocytes.