Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections1,2. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization3-6, but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes, mediated by receptors including Frizzled 1/2/7 (FZD1/2/7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB action stimulates secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin (DT), into peptidergic sensory neurons that express exogeneous DT receptor (an approach we termed toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP, or the SP receptor (NK1R) show reduced pathology in both models of cecal TcdB injection and CDI. Blocking SP or CGRP signaling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.