Alzheimer's disease (AD) is an irreversible neurodegenerative disease that may cause neurotoxicity and imbalance in gut microbiota. A polysaccharide derived from Sparassis crispa-1 (SCP-1) acts as a neuroprotective agent in vitro. There is, however, no clarity on the mechanism responsible for SCP-1's neuroprotective effects against AD. In this study, C57BL/6J male mice were treated with D-galactose and AlCl3 to establish an animal model of AD, followed by treatment with SCP-1. As evidenced by behavioral tests and brain pathology, SCP-1 treatment ameliorated learning deficits and defective spatial recognition, reduced amyloidogenesis, and modulated the neurotransmitter levels (γ-aminobutyric acid, glutamate, and acetylcholine) in the brain of AD mice. The results of 16S rRNA sequencing revealed that SCP-1 reshaped the gut microbiota composition, especially by promoting the proliferation of butyrate-producing genera, such as Intestinaimonas, [Eubacterium] ventriosum group, Lachnospiraceae_UCG_010, and Lachnospiraceae_UCG_001, and suppressing the growth of inflammation-related bacteria (i.e., Escherichia/Shigella). Furthermore, SCP-1 significantly attenuated inflammation by reducing the levels of inflammatory cytokines, maintaining intestinal barrier function, inhibiting glial activation, and decreasing the expression of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB). Collectively, our findings suggest that SCP-1 may prevent the development of AD via modulation of gut microbiota and suppression of inflammation, for a potential application in preventing or managing AD.