Influenza virus infection can alter the composition of the gut microbiota, while its pathogenicity can, in turn, be highly influenced by the gut microbiota. However, the details underlying these associations remain to be determined. The H7N9 influenza virus is an emerging zoonotic pathogen which has caused the death of 616 humans and has incurred huge losses in the poultry industry. Here, we investigated the effects of infection with highly pathogenic H7N9 on gut microbiota and determined potential anti-influenza microbes. 16S rRNA sequencing results show that H7N9 infection alters the mouse gut microbiota by promoting the growth of Akkermansia, Ruminococcus 1, and Ruminococcaceae UCG-010, and reducing the abundance of Rikenellaceae RC9 gut group and Lachnoclostridium. Although the abundance of Akkermansia muciniphila is positively related to H7N9 infection, the oral administration of cultures, especially of pasteurized A. muciniphila, can significantly reduce weight loss and mortality caused by H7N9 infection in mice. Furthermore, oral administration of live or pasteurized A. muciniphila significantly reduces pulmonary viral titers and the levels IL-1β and IL-6 but enhances the levels of IFN-β, IFN-γ, and IL-10 in H7N9-infected mice, suggesting that the anti-influenza role of A. muciniphila is due to its anti-inflammatory and immunoregulatory properties. Taken together, we showed that the changes in the gut microbiota are associated with H7N9 infection and demonstrated the anti-influenza role of A. muciniphila, which enriches current knowledge about how specific gut bacterial strains protect against influenza infection and suggests a potential anti-influenza probiotic.