Dengue virus (DENV) causes a variety of difficult‐to‐treat diseases that threaten almost half of the world's population. Currently, no effective vaccine or antiviral therapy is available. We have examined a series of synthetic resveratrol analogs to identify potential anti‐DENV agents. Here, we demonstrate that two resveratrol analogs, PNR‐4‐44 and PNR‐5‐02, possess potent anti‐DENV activity with EC50 values in the low nanomolar range. These two resveratrol analogs were shown to mainly target viral RNA translation and viral replication, but PNR‐5‐02 is also likely to target cellular factors inside host cells. Although the precise molecular mechanism(s) mediating anti‐DENV activities have not been elucidated, further structure‐guided design might lead to the development of newer improved resveratrol derivatives that might have therapeutic value. J. Med. Virol. 89:397–407, 2017. © 2016 Wiley Periodicals, Inc.