Alzheimer’s disease (AD) is a common neurodegenerative disease, and oxidative stress induced by amyloid β-protein (Aβ) deposition is the key cause of neuronal apoptosis in AD patient. Hydroxy-α-sanshool (HAS) is the predominant flavour substances in the pericarp of Zanthoxylum bungeanum Maxim. (Rutaceae family), which is a known condiment food and herbal medicine in China. We attempt to comprehensively elucidate the pathway and related mechanisms of HAS therapy on AD through in vivo and in vitro experiments. The results showed that HAS could inhibit cell apoptosis, suppress the reactive oxygen species (ROS), and increase the antioxidative enzymes in Aβ1–42 induced HT22 cells. In vivo, HAS attenuated the learning and memory impairment in senescence-accelerated mouse prone 8 (SAMP8) mice, and protected neuronal cells in hippocampus. Interestingly, the 16S rRNA gene sequencing results showed HAS could restore the richness and diversity of the intestinal microbiota, reduce the abundance of Lactobacillus, and increase the abundance of Bateroides and Parabacteroides. Moreover, the contents of 10 metabolites were significantly changed after HAS treatment, which was beneficial to treat AD. In conclusion, HAS could inhibit apoptosis in nerve cells by attenuating Aβ induced oxidative stress level, while it can also influence the metabolic pathways and affect the gut microbiota composition of AD mice.