Objective To investigate the effects of polysaccharides from wine-processed Polygonatum sibiricum (PSPW) on the behavioral performance and antioxidant indices of Alzheimer’s disease (AD) transgenic D.melanogaster, and evaluate its therapeutic effect on AD. Methods Amyloid β42(Aβ42 ) transgenic D. melanogaster were divided randomly into model, and low, medium, and high dose PSPW groups. w1118 D. melanogaster with the same genetic background as the control group. After 28 d of intervention, the lifespan, climbing ability, and olfactory memory were evaluated systematically. Aβ1-42 and malondialdehyde (MDA) levels in brain tissue, superoxide (SOD) and catalase (CAT) activities, and the expression levels of antioxidant genes in the Keap1 / Nrf2 signaling pathway were detected by ELISA and qPCR. Results Behavioral studies showed that AD transgenic D. melanogaster had a significantly shorter lifespan and significantly impaired climbing and olfactory memory abilities compared with the control group. PSPW significantly improved the above behavioral indicators compared with the model group.Regarding antioxidant indicators, brain tissue levels of Aβ1-42 and MDA levels were significantly increased in the model group, while SOD and CAT activities were significantly decreased. Medium and high dose PSPW group significantly reduced Aβ1-42 and MDA levels, increased SOD and CAT activities, and enhanced antioxidant capacity, while D. melanogaster in the low-dose PSPW group showed an improved but non-significant trend. Detection of antioxidant genes in the Kelch-like ECH-associated protein 1 (Keap1) / nuclear factor erythroid 2-related factor 2 (Nrf2) pathway showed that Keap1 expression was increased in the model group, while Nrf2, gamma-glutamylcysteine synthetase (GCL), and glutathione S-transferase S1 ( gsts1) expression were decreased. High dose PSPW group significantly down-regulated Keap1 and up-regulated Nrf2, GCL, and gsts1 expression, while the medium and low dose PSPW groups showed an activation trend but no significant difference. Conclusions PSPW regulate the Keap1 / Nrf2 antioxidant pathway, enhance antioxidant enzyme activities, reduce the accumulation of oxidative products, and achieve the therapeutic effects of reducing Aβ deposition in AD transgenic D. melanogaster and improving motor and memory dysfunctions.