Sjögren’s disease (SjD) is an autoimmune disease that affects exocrine tissues and is characterized by increased apoptosis and decreased expression of membrane proteins involved in secretory function, such as Na-K-Cl cotransporter-1 (NKCC1), in salivary and lacrimal glands. Although the pathogenic mechanism triggering SjD is not well understood, overexpression of lysosome-associated membrane protein 3 (LAMP3) is associated with the disease in a subset of SjD patients and the development of SjD-like phenotype in mice. In this study, histological analysis of minor salivary glands of SjD patients suggested that LAMP3-containing material is being ejected from cells. Follow-on in vitro experiments with cells exposed to larger extracellular vesicles (LEVs) derived from LAMP3-overexpressing cells showed increased apoptosis and decreased NKCC1 expression. Proteomics identified LAMP3 as a major component of LEVs derived from LAMP3-overexpressing cells. Live-cell imaging visualized release and uptake of LAMP3-containing LEVs from LAMP3-overexpressing cells to naïve cells. Furthermore, experiments with recombinant LAMP3 protein alone or complexed with Xfect protein transfection reagent demonstrated that internalization of LAMP3 was required for apoptosis in a caspase-dependent pathway. Taken together, we identified a new role for extracellular LAMP3 in cell-to-cell communication via LEVs, which provides further support for targeting LAMP3 as a therapeutic approach in SjD.