AbstractBackgroundAcanthopanax senticosus(AS) is a medicinal and food plant with many physiological functions, especially nerve protection. Its extract has many functional components, including polysaccharides, flavonoids, saponins, and amino acids. Our previous study indicated thatASextract protected against nerve damage caused by radiation. However, little is known about the gut‐brain axis mechanism of AS and its impact on radiation‐induced learning and memory impairment.MethodIn60Co‐γ ray‐irradiated mice, we investigated the changes in behavior, neurotransmitters and gut microbiota after different days of administration ofASextract as a dietary supplement.ResultsTheASextract improved learning and memory ability in mice, and the neurotransmitter levels in the hippocampus and colon started to change from the 7th day, which accompanied changes of the gut microbiota, a decreased abundance ofHelicobacteron the 7th day and an increased abundance ofLactobacilluson the 28th day. Among the marker bacteria,RuminococcusandClostridialeswere associated with 5‐HT synthesis, and Streptococcus were associated with 5‐HT and ACH synthesis. In addition, theASextract increased the tight junction protein, inhibited inflammation levels in colon, and even increased the relative protein expression of BDNF and NF‐κB and decreased the relative protein expression of IκBα in the hippocampus of irradiated mice.ConclusionThese results will lay the foundation for further study on the mechanism of the gut‐brain axis ofASin preventing radiation‐induced learning and memory impairment.