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Previous reports suggest that rotensin II (UII) and its G protein-coupled receptor (GPR14) involve in inflammatory mediation, while the effects of UII/GPR14 in liver inflammatory response are not fully illustrated. Thus, in this study, urantide, a special antagonist of GPR14, was used to investigate the effects of UII/GPR14 on carbon tetrachloride (CCl4) induced liver injury in mice. The results showed that CCl4 upregulated liver UII and GPR14 expression. Meanwhile, CCl4 caused liver injury, inflammation and oxidative stress. Injection of urantide alleviated CCl4-induced inflammatory response and oxidative stress, which might further exhibit a hepatoprotective effect. In conclusion, UII/GPR14 may serve as a potential target for therapeutic intervention in liver injury.