SummaryResveratrol is a natural phenolic product found in some plants in response to stress and has been linked to the many health benefits of red wine. Over the past several decades, a great deal of research has identified diverse biological roles associated with resveratrol, including anti‐oxidant, anti‐proliferation, anti‐inflammation, anti‐cancer, anti‐fungal, and antiviral activities. Such biological activities of resveratrol are likely mediated through multiple cellular targets or pathways, such as sirtuins, a family of NAD+‐dependent deacetylases. In this treatise, the literatures focusing on the roles of resveratrol and sirtuins in modulating infections by a broad‐spectrum of viruses are reviewed, with an emphasis on its potential antiviral mechanisms. A working model about the effects of resveratrol on virus infection is proposed to stimulate further researches on this exciting topic. Copyright © 2015 John Wiley & Sons, Ltd.