Objective To investigate the effects of adenosine A2A receptor agonist CGS21680 on the concanavalin (ConA)-induced acute liver injury of mice and possible mechanisms. Methods C57BL/6 male mice were randomly divided into the ConA group and CGS21680+ConA group. Mice of the ConA group were given ConA of 20 mg/kg by caudal vein injection. Mice of the CGS21680+ConA group were given adenosine A2A receptor agonist CGS21680 of 2.1 mg/kg by intraperitoneal injection and then were given ConA of 20 mg/kg by caudal vein injection after 10 min. Levels of serum ALT, AST, IFN-γ, IL-4, and TNF-α were detected. Pathologic changes of liver tissue were measured under the optical microscope and the level of hepatic injury was evaluated. Expressions of IFN-γ and IL-4 of CD4+T cells in mononuclear cells (MNCs) were detected by the flow cytometry. Results Compared to the ConA group, levels of serum ALT, AST, IFN-γ, IL-4, and TNF-α of the CGS21680+ConA group significantly decreased; inflammatory cell infiltration of liver tissues significantly decreased; hepatic injuries were mild; and expressions of IFN-γ and IL-4 of CD4+T cells in liver tissues decreased. Conclusion Pretreatment by the adenosine A2A receptor agonist CGS21680 can significantly relieve the ConA-induced acute hepatic injury of mice. This may be relevant to activating A2A receptor on the surface of CD4+ T cells by the CGS21680 and inhibiting the release of proinflammatory factors.