The detection of internal chemicals by interoceptive chemosensory pathways is critical for regulating metabolism and physiology1. The molecular identities of interoceptors, and the functional consequences of chemosensation by specific interoceptive neurons, remain to be fully described. The pharyngeal neuronal network of Caenorhabditis elegans is anatomically and functionally analogous to the mammalian enteric nervous system2,3. Here we show that the I3 pharyngeal enteric neuron responds to cations via an I3-specific ionotropic receptor to regulate salt stress tolerance. The GLR-9 ionotropic receptor and the GLR-7 IR25a co-receptor orthologue localize to the gut lumen-exposed sensory ending of I3, and are necessary and sufficient for salt sensation. Salt detection by I3 protects specifically against high-salt stress, as glr-9 mutants show reduced tolerance of hypertonic salt but not of sugar solutions, with or without prior acclimatization. Whereas cholinergic signalling from I3 promotes tolerance of acute high-salt stress, peptidergic signalling from I3 during acclimatization is essential for resistance to a subsequent high-salt challenge. Transcriptomic and reporter gene analyses show that I3 modulates salt tolerance in part by regulating the expression of salt stress response genes in distal tissues. Correspondingly, mutations in a subset of salt- and GLR-9-regulated genes reduce salt stress resistance. Our results describe the mechanisms by which chemosensation mediated by a defined enteric neuron regulates physiological homeostasis in response to a specific abiotic stress.