Objective To investigate the effects of polysaccharides from wine-processed polygonatum sibiricumon the behavioral performance and antioxidant indices of AD transgenic D.melanogaster, and evaluate its therapeutic effect on AD. Methods w1118 D.melanogaster with the same genetic background were used as the control group. Aβ42 transgenic D.melanogaster were randomly divided into the model group, low, medium, and high-dose Polysaccharides from wine-Processed Polygonatum sibiricum groups. After 28 days of intervention, the lifespan, climbing ability, and olfactory memory ability of the D.melanogaster were systematically evaluated; ELISA and qPCR techniques were used to detect the contents of Aβ1-42 and MDA in brain tissue, as well as the activities of SOD and CAT, and the expression levels of antioxidant genes in the keaP1/Nrf2 signaling Pathway. Results Behavioral studies showed that compared with the control group, the lifespan of AD transgenic D.melanogaster was significantly shortened, and their climbing and olfactory memory abilities were significantly impaired. After intervention with polysaccharides from wine-processed polygonatum sibiricumon, the above behavioral indicators were significantly improved compared with the model group. The analysis of antioxidant indicators indicated that the contents of Aβ1-42 and MDA in the brain tissue of the model group were significantly increased, while the activities of SOD and CAT were significantly decreased; medium and high-dose polysaccharides from wine-processed polygonatum sibiricumon could significantly reduce the levels of Aβ1-42 and MDA, increase the activities of SOD and CAT, enhance antioxidant capacity, and the low-dose group showed an improvement trend but no statistical difference. The detection of antioxidant genes in the keap1/Nrf2 Pathway showed that the expression of keap1 was increased in the model group, while the expressions of Nrf2, GCL, and gsts1 were decreased; high-dose polysaccharides from wine-processed polygonatum sibiricumon could significantly down-regulate the expression of keap1 and up-regulate the expressions of Nrf2, GCL, and gsts1, while medium and low-dose groups showed an activation trend but no statistical difference. Conclusion Polysaccharides from wine-Processed Polygonatum sibiricumon regulate the keap1/Nrf2 antioxidant Pathway, enhance antioxidant enzyme activities, reduce the accumulation of oxidative products, and achieve the therapeutic effect of reducing Aβ deposition in AD transgenic D.melanogaster and improving motor and memory dysfunction.