Objective: The efficacy of total glucosides of paeony (TGP) in the treatment of Sj?gren's syndrome (SS) and its relationship with inhibition of NLRP3 inflammasome activation were investigated, so as to clarify the novel mechanisms of TGP on treatment of SS. Methods: Female non-obese diabetic (NOD) mice were selected as the model of SS. The NOD mice were intragastric administrated with TGP （400mg·kg-1）for 1 month. The saliva flow rates of mice were measured. The lymphocyte infiltration in submandibular gland was determined. The NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation of spleen was detected. In vitro, the NLRP3 inflammasome was activated in cultured splenocytes with or without 100ug/ml TGP treatment. Then, the NLRP3 inflammasome activation was determined by RT-qPCR and Western blot. Results: Compared with the mice of control group, the saliva flow rates were significantly increased（P＜0.05） and the lymphocyte infiltration in submandibular gland was significantly reduced in NOD mice of TGP treatment group. The NLRP3 inflammasome of spleen was inhibited in NOD mice with TGP treatment（P＜0.05）. In vitro, the NLRP3 inflammasome activation of splenocytes was also suppressed by TGP(P＜0.05). Conclusion: Our results showed that TGP alleviated SS-like symptoms in NOD mice and these beneficial effects were related to inhibition of NLRP3 inflammasome activation. Our findings not only uncovered the novel mechanisms of therapeutic effects of TGP in SS, but also provided new evidences for application of TGP in treatment of SS patients.