Sjögren's syndrome (SS) is a chronic autoimmune disease with exocrine glands disorder. Our previous work demonstrated the protective effect of Dendrobium officinale polysaccharides (DP) both on the phenotypes of patients and animal model with SS. In this study, we expand these observations to explore the possible mechanisms. The experimental SS mice model was established with or without the administration of DP (20 mg/ml). The time frame of lymphocytes infiltration, apoptotic indicators such as Bax, Bcl-2 and caspase-3 were determined in submandibular gland (SG), as well as the subsequent mRNA expression of cytokines such as TNF-α, IL-1beta and IL-6. The expression and localization of aquaporin-5 (AQP-5) was examined by Western blot and immunofluorescent staining. As the result, DP could suppress the progressive lymphocytes infiltration and apoptosis, and balance the chaos of pro-inflammatory cytokines in the SG. Further, DP ameliorated the abnormalities of AQP-5 and maintained its functional importance of saliva secretion. In addition, the protection of AQP-5 by DP from human TNF-α was supported by an in vitro study on A-253 cell line. Our study further supported the efficacy of DP as the promising candidate for the therapy of SS.