Objective To study the effects of Dangshen Yuanzhi powder microemulsion on apoptosis of hippocampal neurons in mice with cortical dementia induced by D-galactose and sodium nitrite based on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signal pathway. Methods Sixty ICR mice were randomly divided into 6 groups:normal group, model group, biocompatible microemulsion group, piracetam group, low-dose group of Dangshen Yuanzhi powder microemulsion, and high-dose group of Dangshen Yuanzhi powder microemulsion, with 10 mice in each group. Except for the normal group, the other 5 groups were intraperitoneally injected with D-galactose (120 mg/kg) and sodium nitrite (54 mg/kg) to establish mouse models of cortical dementia. Distilled water, biocompatible microemulsion (10 mL/kg), piracetam (0.63 g/kg), low- and high-doses of Dangshen Yuanzhi powder microemulsion (equivalent to 8.58 g/kg and 17.16 g/kg of raw medicine) were given by gavage, once a day for 6 weeks. Memory ability was examined by Morris water maze test, pathomorphological changes were observed by hematoxylin-eosin staining, the changes of Nissl bodies of neurons in the hippocampal cortex were observed by Nissl staining, the expression of PI3K, Akt and mTOR in the hippocampal cortex was observed by immunohistochemistry, and the expression of doublecortin (DCX) and the growth of newborn neurons in hippocampal cortex were observed by immunofluorescence. Results Compared with the model group, the learning and memory ability of mice with cortical dementia was significantly improved in the low- and high-dose groups of Dangshen Yuanzhi powder microemulsion, the pathological morphology of the hippocampal cortex was obviously improved, the neurons were round and dense, the contents of Nissl bodies of neurons were abundant, the expression of PI3K, Akt and mTOR was significantly decreased, the expression of DCX was significantly increased, the distribution of newborn neurons was dense, and extended synapse was increased. Conclusion Low- and high-doses of Dangshen Yuanzhi powder microemulsion can induce autophagy by inhibiting PI3K/Akt/mTOR signaling pathway, reduce neuronal damage, induce neuronal regeneration, and improve learning and memory ability in mice with cortical dementia induced by D-galactose and sodium nitrite. Considering efficacy and toxicity, low-dose (the clinical equivalent dose) of Dangshen Yuanzhi powder microemulsion should be selected.