It is well known that H. cordata water extracts (HCWEs) exhibit anti-HSV activity and the inhibitory activity might affect the NF-κB activation at 6 h.p.i. hereafter which was defined as the second-wave of NF-κB activation in HSV infection [17, 27, 28]. However, the molecular mechanisms involved in anti-HSV activity of HCWEs are not thoroughly explored yet. Whether HCWEs execute the inhibitory activity through targeting virus particles, affecting cellular components or both is still unclear. However, the understanding of mechanism-of-action (MOA) and identification of targets are the most critical requisites in new drug development. In this study, we focused on elucidating MOA of HCWEs in addition to suppressing NF-κB activation and identifying the effective component of HCWEs against HSV infection.