Purpose: Liver tissue regeneration is vital in the restoration of liver function after hepatectomy and liver transplantation. Dexmedetomidine is a highly selective alpha2-adrenergic receptor (A2R) agonist, whichis regarded as a sedative and analgesic medication that is frequently used intra- and postoperatively in hepatic surgery. Owing to its critical role in the protection of multiple organs, the purpose of this study is to investigate the effects of dexmedetomidine on liver regeneration. Methods:Dexmedetomidine 25 μg.kg-1 was injected intraperitoneally 30 minutes before a 70% hepatectomy performed in mice. Blood and liver samples were obtained for analysis after 48 hours. Mouse primary hepatocytes (MPHMPHs) were incubated with 10 μM dexmedetomidine for 24 hours, then analyzed for cell proliferation from mRNA and protein levels. Transcriptome sequencing revealed the potential mechanism of dexmedetomidine promoting liver regeneration, verified by western blot analysis. Loss of function analysis was performed using the selective corresponding antagonist of Dexmedetomidine . Results:25 μg.kg-1 Ddexmedetomidine significantly promoted mouse liver regeneration in vivo. The liver/body weight ratio was elevated following dexmedetomidine preconditiontreatment. ImmunohistochemistryProliferative markers of Ki67, PCNA and cyclin-D1 suggested more hepatocytes enter a state of proliferatimore cell proliferationon in dexmedetomidine group via immunohistochemistry. These effects were also phenocopied in vitro Incubating withwhere 10 µM dexmedetomidine increased MPH proliferation in vitro, detected by Edu and Ki67 immunofluorescence staining. The expression of cyclins, PCNA mRNA, protein expression levels of cyclins and PCNA were higher with dexmedetomidine treatment in vivo and in vitro. The p-AKT, p-GSK3beta and beta-catenin expression levels were elevated by dexmedetomidine. The effect of dexmedetomidine on MPH proliferation and p-AKT, p-GSK3beta and beta-catenin expressionse phenomenon was blocked by atipamezole (ATI, alpha2 adrenoceptor antagonist) pretreatment. Conclusion:Dexmedetomidine activates AKT/GSK3beta/beta-catenin pathway to promote enhance liver regeneration via binding the alpha-2 adrenoreceptor, which would shed light on a potential therapeutic clinical role to protect liver function in a broad of hepatic surgery.