Oxygen (O₂) sensing by the carotid body is critical for maintaining cardiorespiratory homeostasis during hypoxia. Hydrogen sulfide (H₂S) signaling is implicated in carotid body activation by low O₂. Here, we show that persulfidation of olfactory receptor 78 (Olfr78) by H₂S is an integral component of carotid body activation by hypoxia. Hypoxia and H₂S increased persulfidation in carotid body glomus cells and persulfidated cysteine²⁴⁰ in Olfr78 protein in heterologous system. Olfr78 mutants manifest impaired carotid body sensory nerve, glomus cell, and breathing responses to H₂S and hypoxia. Glomus cells are positive for GOlf, adenylate cyclase 3 (Adcy3) and cyclic nucleotide–gated channel alpha 2 (Cnga2), key molecules of odorant receptor signaling. Adcy3 or Cnga2 mutants exhibited impaired carotid body and glomus cell responses to H₂S and breathing responses to hypoxia. These results suggest that H₂S through redox modification of Olfr78 participates in carotid body activation by hypoxia to regulate breathing.