Abstract The diarrheal disease cholera remains a global threat. However, knowledge of the innate immune defenses in the small intestine that protect against the causative agent, Vibrio cholerae, is limited. Here, single-cell RNA-sequencing of epithelial and immune cells mapped gene expression patterns in the infant mouse small intestine and revealed changes in response to V. cholerae infection and treatment with an IL22 Fc-fusion protein. Infection increased the abundance of an enterocyte subtype that highly expressed defense-associated functions and stimulated production of IL22, a cytokine linked to epithelial integrity, from group 3 innate lymphoid cells. Administration of IL22Fc increased production of vibriocidal Reg3β from enterocytes and the abundance of secretory lineage and Muc2-producing goblet cells, which secreted mucus into the intestinal crypts, impairing V. cholerae association with the epithelium. These IL22-mediated responses limited V. cholerae intestinal colonization and protected mice from diarrhea and death. These observations suggest enterocyte specialization in mucosal defense, identify mechanisms of IL22-mediated protection, and point to host-directed approaches for cholera therapeutics.