This study addresses the scarcity of data on the engraftment and functional capabilities of solid tissue-derived human adult epithelial stem cells, focusing on salivary gland (SG) stem/progenitor cells. The research demonstrates the isolation of these cells, showcasing their in vitro self-renewal and differentiation into multilineage organoids at the single-cell level. The study also reveals in vivo functionality, long-term engraftment, and functional restoration in a xenotransplantation model. Transplanted human salisphere-derived cells successfully restored saliva production and significantly improved regenerative potential in irradiated SGs. Moreover, the enrichment of cells expressing c-Kit enhanced regenerative potencies. The interaction between transplanted cells and the recipient SG appears to play a role in functional recovery. This study highlights the therapeutic potential of salisphere cell therapy for treating xerostomia.