Objective：To study the therapeutic effect and mechanism of Lidocaine（Lido）on cardiac damage（Doxorubicin）in mice. Methods：Thirty -two SPF mice were randomly divided into four groups（n=8）：saline group，Dox group，Dox + Lido group，and Lido group. The observation and detection of body weight，survival rate，Doppler flow imaging，ECG，cardiac ultrasound，plasma creatine kinase isoenzyme（CreatineKinase-MB，CK-MB），Troponin I（Cardiac troponin I，cTnI），tissue factor（TF）in the myocardial tissue， matrix metalloproteinase 9（MMP-9），phosphorylated adenosine 5’-monophosphate-activated protein kinase（p-AMPK），gap junction protein（connexin43，Cx43），inhibitor of cytokine signaling 3（recombinant suppressors of cytokine signaling 3，SOCS3）content. Results：Compared with the saline group，the mice in the Dox group showed the decreased body weight and survival rate，reduced heart rate，limited QRS wave time，prolonged QT interval，cardic contracture，small cardiac cavity，and increased expression of plasma CK- MB and cTnI but decreased expression of p-AMPK，SOCS3 and Cx43. Compared with the Dox group，mouse weight，survival rate and heart rate were increased in the Dox + Lido group. Moreover，the QRS wave time and the QT interval as well as the plasma expression of CK-MB and cTnI were normal in the Dox + Lido group mice. Also，no significant changes in cardiac size were observed. The expression of TF and MMP-9 decreased，but p-AMPK，SOCS3 and Cx43 levels increased in the heart tissues of the Dox+Lido treated mice. Conclusion：Lidocaine can alleviate acute doxorubicin-induced cardiac injury through activation of the p-AMPK/SOCS 3/Cx43 signaling pathway and inhibiting the high TF/MMP-9 expression.