Amiodarone (AM) is one of the most effective antiarrhythmic drugs and normally administrated by intravenous infusion which is liable to cause serious phlebitis. The therapeutic drugs for preventing this complication are limited. Intermedin (IMD), a member of calcitonin family, has a broad spectrum of biological effects including anti‐inflammatory effects, antioxidant activities, and antiapoptosis. But now, the protective effects of IMD against amiodarone‐induced phlebitis and the underlying molecular mechanism are not well understood. In this study, the aim was to investigate the protective efficiency and potential mechanisms of IMD in amiodarone‐induced phlebitis. The results of this study revealed that treatment with IMD obviously attenuated apoptosis and exfoliation of vascular endothelial cells and infiltration of inflammatory cells in the rabbit model of phlebitis induced by intravenous infusion of amiodarone compared with control. Further tests in vitro demonstrated that IMD lessened amiodarone‐induced endothelial cell apoptosis, improved amiodarone‐induced oxidative stress injury, reduced inflammatory reaction, and activated the Wnt/β‐catenin signal pathway which was inhibited by amiodarone. And these effects could be reversed by Wnt/β‐catenin inhibitor IWR‐1‐endo, and si‐RNA knocked down the gene of Wnt pathway. These results suggested that IMD exerted the protective effects against amiodarone‐induced endothelial injury via activating the Wnt/β‐catenin pathway. Thus, IMD could be used as a potential agent for the treatment of phlebitis.