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Abstract Pandemic and endemic strains ofVibrio choleraearise from toxigenic conversion by the CTXφ bacteriophage, a process by which CTXφ infects nontoxigenic strains ofV. cholerae.CTXφ encodes the cholera toxin, an enterotoxin responsible for the watery diarrhea associated with cholera infections. Despite the critical role of CTXφ during infections, signals that affect CTXφ‐driven toxigenic conversion or expression of the CTXφ‐encoded cholera toxin remain poorly characterized, particularly in the context of the gut mucosa. Here, we identify mucin polymers as potent regulators of CTXφ‐driven pathogenicity inV. cholerae.Our results indicate that mucin‐associatedO‐glycans block toxigenic conversion by CTXφ and suppress the expression of CTXφ‐related virulence factors, including the toxin co‐regulated pilus and cholera toxin, by interfering with the TcpP/ToxR/ToxT virulence pathway. By synthesizing individual mucin glycan structuresde novo, we identify the Core 2 motif as the critical structure governing this virulence attenuation. Overall, our results highlight a novel mechanism by which mucins and their associatedO‐glycan structures affect CTXφ‐mediated evolution and pathogenicity ofV. cholerae, underscoring the potential regulatory power housed within mucus.