The epidermal growth factor receptor (EGFR) is a promising therapeutic target in bladder cancer (BC). Thus, the development of novel EGFR inhibitor is urgently needed. We computationally screened 3,167 worldwide approved small molecule drugs for potential wild-type EGFR inhibitors. The antibiotic and antiprotozoal agent dibromopropamidine dihydrochloride exhibited the highest cytotoxic activity in a dose- and time-dependent manner, with the IC50 similar to that reported for the FDA approved EGFR inhibitors, gefitinib and higher than afatinib. We demonstrated that dibromopropamidine dihydrochloride inhibited the wild type EGFR kinase activity while had no effect on HER-2 kinase activity. Furthermore, dibromopropamidine dihydrochloride treatment significantly promoted cell apoptosis and inhibited the phosphorylation of EGFR and its downstream proteins AKT and ERK in a dose-dependent manner. Structural analysis of the predicted binding conformation suggested that dibromopropamidine dihydrochloride binds to EGFR at ATP binding site via the formation of two hydrogen bonds with GLY796 and ASP855. Finally, dibromopropamidine dihydrochloride significantly suppressed tumor growth in vivo. These results suggest for the first time that dibromopropamidine dihydrochloride is an EGFR inhibitor, and a promising anticancer candidate drug for the treatment of BC.