The plant polyphenol, resveratrol (Resv, 3,4,5-trihydroxystilbene), naturally occurring in a number of fruits and other food products, has been extensively studied over the last two decades for its beneficial properties. Recently, its possible topical use in ameliorating skin conditions has also been proposed; however, its role in preventing cigarette smoke (CS)-induced keratinocyte damage has not been investigated yet. Because of its peculiar location, cutaneous tissue is constantly exposed to several environmental stressors, such as CS. Many compounds presented in CS, have been shown to induce, directly or indirectly, cellular oxidative stress (OS) and inflammation via the production of ROS and lipid peroxidation compounds, among which 4HNE has been shown to be one of the most reactive. In this study, we have shown that resveratrol (at a dose of 10 μM) can decrease CS-induced ROS and carbonyl formation in human keratinocytes. In addition, pre-treatment with resveratrol prevented the induction of TRPA1 expression (mRNA and protein levels), a known receptor involved in cellular differentiation and inflammation, which has been recently shown to be activated by 4HNE. Finally, in keratinocytes, resveratrol could increase the expression of MsrA, enzyme involved in cell defence against oxidative protein damage. The present study further confirms the idea that the topical use of resveratrol can provide a good defence against CS-induced skin damage.