In this study, we characterize a series of afatinib-derivative TKI compounds, evaluate the antiviral effects of these compounds against DENV and ZIKV infection in vitro and in vivo, demonstrate the superior therapeutic efficacy of compound L3 (compared to other TKIs), identify that HER2 activities are involved in DENV and ZIKV replication, and describe a potential potent therapeutic drug against emerging flaviviral infections. This evidence concerns the gene ERBB2 and Zika virus infectious disease.