The herpes simplex virus (HSV) is a common human virus affecting many people worldwide. HSV infections manifest with lesions that occur in different parts of the body, including oral, ocular, nasal, and genital skin and mucosa. In rare cases, HSV infections can be serious and lethal. Several anti-HSV drugs have been developed, but the existence of mutant viruses resistant to these drugs led to the individuation of novel antiviral agents. Plant-derived bioactive compounds, and more specifically polyphenols, have been demonstrated to exert marked anti-HSV activity and, among these, resveratrol (RSV) would be considered a good candidate. The purpose of this manuscript is to review the available literature elucidating the efficacy of RSV against HSV and the main demonstrated mechanisms of action.