Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter that exerts pleiotropic neuromodulatory, anti-inflammatory, cytoprotective, and trophic effects within the central nervous system. Objectuves: This study investigated whether chronic inhalation of naturally H₂S-rich sulphureous water, a non-invasive and clinically applicable intervention, exerts neuroprotective effects in 5XFAD mice, a transgenic model of severe AD pathology. Methods: Two-month-old male and female wild-type and 5XFAD mice underwent daily inhalation of saline or sulphureous water for eight weeks. Sulphureous water exposure was well tolerated and did not impair baseline learning or memory in either genotype. A detailed analysis of swim trajectories revealed selective enhancement of spatially accurate navigation strategies in sulphureous water-exposed 5XFAD female mice, with nearly a threefold increase in effective search behaviors, whereas male mice showed no treatment-specific effects. In addition, sulphureous water inhalation significantly reduced the number and area of 6E10⁺ and 11A1⁺ amyloid-β plaques in corticohippocampal regions and decreased cortical microglia number. Transcriptional profiling of cortical tissue revealed strong genotype-dependent upregulation of microglial, inflammatory, and stress-response genes. Sulphureous water exposure selectively modulated inflammatory and stress-response genes, including Cd11b, Cst, Sod1, Tgfb1, and Hsp90a, with distinct genotype-dependent interactions. Results: Overall, chronic inhalation of naturally H₂S-rich sulphureous water during the prodromal phase of AD-like pathology mitigated early amyloid burden, reduced cortical microgliosis, and improved qualitative aspects of spatial navigation, particularly in female mice. Conclusions: These findings warrant further translational investigation of sulphureous water inhalation as a potential preventive or disease-modifying strategy for AD in humans.