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BACKGROUND Three kinds of diet containing chicken protein isolate (CPI), bovine milk protein isolate (BMPI), and soy protein isolate (SPI), respectively, were designed to investigate the influences of proteins on cognitive levels and related mechanisms in mice. RESULTS A Morris water maze (MWM) test showed that the SPI group had a higher cognitive level than the BMPI group. Immunohistochemical staining and chemical analysis of the hippocampus showed that the SPI group had higher synaptophysin expression, doublecortin-positive cell proportion, superoxide dismutase activity, and lower malondialdehyde content compared with the BMPI group. The same parameters in the CPI group were between those of the BMPI and SPI groups. Microbiome sequencing indicated that the three groups differed significantly at the phylum, genus, and species levels, with higher microbial alpha diversity in the CPI and SPI groups. The association of intestinal microbiota with cognitive improvement was also assessed. The present study suggests that soy protein may increase cognitive function by the gut-brain axis. CONCLUSION In contrast with CPI and BMPI, SPI had a better effect on improving the cognitive level in mice, which was achieved through the regulation of hippocampal neural growth, oxidative stress, and intestinal microbiota. © 2022 Society of Chemical Industry.