We previously reported a novel danshensu analogue known as ADTM, which exhibited strong protective effects against oxidative stress-induced cellular injury and acute ischemic myocardial infarct in rat; however, the exact protein target of ADTM has not been fully characterized. In the present study, a biotin-conjugated ADTM analogue (BAA) was employed as molecular probe to identify its protein targets. BAA exhibited similar protective effect against oxidative stress-induced cell injury in H9c2 cardiomyoblast. A chemical proteomic approach identified ERp57 as the specific target for BAA. Further evaluation with Western blot and immunofluorescence staining assays confirmed the direct interactions between BAA and ERp57. Moreover, BAA displayed potent inhibitory effect on the catalytic activity of ERp57 in the insulin reduction assay. Molecular docking showed that BAA bound at the active site of ERp57. These data suggested that ERp57 is a potential target of cardioprotective danshensu analogues, and provided the basis for the further optimization of the cardioprotective compounds.