Objective: To study the therapeutic effect and corresponding mechanism of lidocaine (Lidocaine, LIDO) on cardiac injury induced by doxorubicin (Doxorubicin, DOX) in mice. Methods: 32 SPF mice were randomly divided into 4 groups (n = 8). The model of acute myocardial injury was constructed by single intra-abdominal injection of DOX 20mg/kg. There were four groups: control group, DOX group, DOX+LIDO group, and LIDO group. The body weight, survival rate, Doppler flow imaging, electrocardiogram, levels of CK-MB, cTn-T, TF, MMP-9, p-AMPK, Cx43 and SOCS3 in each group were measured. Results: Compared with the DOX group, DOX + LIDO group of the mice showed increased body weight and survival, improved heart rate, normalized QRS duration and QT interval, plasma CK-MB and cTn-T values in the normal interval, heart recovery to normal size, decreased TF and MMP-9, and increased expression of p-AMPK, SOCS, and Cx43 in heart tissue. Conclusions: Lidocaine ameliorates doxorubicin-induced cardiotoxicity, possibly through increasing AMPK and subsequent SOCS3 expressions, resulting in Cx43 upregulation.