Objective We investigated mechanisms associated with Polygonum perfoliatum L. extract in relieving a 9-month-old APP / PS1/ tau three-transgenic Alzheimer’s disease model in mice. Methods Male APPSwe / PS1M146 V/ tauP301 L 3xTg-AD 3xTg-AD mice and their background C57BL/ 6J mice were randomly divided into four groups, with 12 mice in eachper group, respectively: a control group (normal saline), a three-turn model control group (normal saline), a three-turn model anesthesia group (normal saline + sevoflurane), and a three-turn model administration group (normal saline + sevoflurane + Polygonum perfoliatum L. extract). All mice were injected with isovolumic saline or 0. 1 μg/4 μL of Polygonum perfoliatum L. extract through the lateral ventricle for 10 consecutive days. The control group inhaled two hours of oxygen, and the anesthetized group and the administration group inhaled two hours of sevoflurane. At 24 hours after the end of anesthesia, six mice in each group were tested for spatial learning and memory in a Morris water maze. Fresh hippocampal tissue was obtained by decapitation from the remaining mice, prepared into a homogenate, and b-amyloid peptide (Aβ) aggregation (Aβ, Aβ1-40, Aβ1-42) was detected by Western blot and by tau protein phosphorylation. The phosphorylation levels of all associated loci (Serine 396, Serine 262 and Threonine 231) were checked as well. The expression of mitochondrial apoptosis signaling pathway genes, including B-cell lymphoma-2 (BcL-2), BcL-2-associated X protein (Bax) and Cysteine-requiring Aspartate Protease (Caspase-3) was detected by Real-time PCR. Results Morris water maze experiments show that sevoflurane has no effect on learning and memory ability in mice, but it does have potential neurotoxicity in mice. Extracts of Polygonum perfoliatum L. can reduce Aβ aggregation and tau protein phosphorylation states in three-transformation mice. Compared with the three-turn model anesthesia group, BcL-2 expression was decreased and Bax and Caspase-3 expression was enhanced in the three-turn model administration group. Conclusions Polygonum perfoliatum L. extract can alleviate mitochondria-associated apoptotic signaling pathways induced by sevoflurane anesthesia, as well as reduce Aβ aggregation, decrease tau protein phosphorylation, and inhibit the apoptosis of mouse hippocampal neurons.