BACKGROUND: Endogenous hydrogen sulfide (HS) and its key generating enzyme, cystathionine β-synthase (CBS), prevent vascular remodeling and damage to target organs during the advancement of hypertension induced by a high-salt diet. OBJECTIVE: The contribution of the HS/CBS pathway to high-salt-induced myocardial fibrosis (MF) was explored, with a focus on the mechanistic involvement of hypoxia-inducible factor-1α (HIF-1α). METHODS: We used primary rat cardiac fibroblasts stimulated with high-salt medium and an MF model induced by a high-salt diet in Dahl salt-sensitive rats. Sodium hydrosulfide (NaHS), a commonly used HS donor, was administered at 100 μmol/L and at 90 μmol/kg to maintain adequate HS levels. An HIF-1α stabilizer, dimethyloxalylglycine (DMOG), was used to maintain the HIF-1α protein level. The HS/CBS pathway was followed using Western blotting and a sulfide-sensitive probe. The extent of MF was examined using histological and immunofluorescence staining techniques, including Sirius red and Masson trichrome. We performed Western blot analysis to measure fibrosis-related protein and HIF-1α protein levels. RESULTS: High-salt exposure reduced HS production and downregulated CBS protein expression in cardiac fibroblasts both and . , the HS donor inhibited the activation of cardiac fibroblasts triggered by high-salt conditions, while , it alleviated MF in salt-sensitive rats. From a mechanistic standpoint, high-salt exposure markedly upregulated HIF-1α expression. However, this increase was reversed by pretreatment with HS. Furthermore, the HIF-1α stabilizer DMOG blocked the HS-induced reduction in HIF-1α protein levels and consequently abolished the antifibrotic effect of HS on cardiac fibroblasts exposed to high-salt conditions. CONCLUSION: In conclusion, HS attenuates high-salt-induced MF by suppressing fibroblast activity and collagen synthesis, potentially via downregulation of HIF-1α.