Background and Purpose: High mobility group box 1 (HMGB1) is a nuclear protein that is released on injury triggers inflammation. This study aims to elucidate the effects of salidroside on diabetes-induced liver inflammation. Experimental Approach: The levels of glucose, inflammatory cytokines and hepatic functional parameters in serum and liver of type 2 diabetic db/db mice were examined. Immunohistochemistry, immunofluorescence and western blot tests were performed to determine the mechanisms underlying the action. Palmitic acid (PA) or HMGB1–stimulated was adopted as an in vitro cell model. Key Results: Salidroside treatment improved glucose tolerance, lipid profiles while decreased the production of inflammatory cytokines. It also reduced the levels of serum biochemical markers. In addition, salidroside inhibited HMGB1 signaling pathway in db/db mice. In the salidroside treatment significantly inhibited PA or HMGB1 induced inflammatory signaling pathway, too. HMGB1 inhibitors and HMGB1 knockdown both hindered PA-induced HMGB1 signaling pathway, showing the same effect as salidroside. Conclusion: Salidroside treatment significantly alleviates insulin resistance, hyperglycemia and hepatic inflammation in db/db mice, and also showed beneficial to PA-stimulated. Salidroside proves to control hyperglycemia and hepatic inflammation via inhibiting HMGB1/RAGE/NF-κB and HMGB1/TLR4/NLRP3 signaling pathways. Funding Statement: This research was supported by National Natural Science Foundation of China (81400800). Declaration of Interests: The authors declare that they have no conflict of interest Ethics Approval Statement: All animal experiments were conducted in accordance with animal ethics of Zhengzhou University.