Pollution, especially cigarette smoke, is a major cause of skin damage. We assessed the effects of the small molecule polyphenol on reversing cigarette smoke induced damage in vitro to relevant skin cells. Keratinocytes (HaCat) cultures were exposed to cigarette smoke and, after 48 hours, IL-1? and IL-8 were measured in cell supernatants. Moreover, TIMP-2 production, apoptosis rate, and senescence ?-galactosidase expression were evaluated in primary human fibroblasts (HFF-1) cultures. Honokiol at 10 ?M reduced IL-1? production by 3.4 folds (p<0.05), and at 10 and 20 ?M reduced IL-8 by 23.9% and 53.1% (p<0.001), respectively, in HaCat keratinocytes. In HFF-1, honokiol restored TIMP-2 production by 96.9% and 91.9% (p<0.001), respectively, at 10 and 20 ?M, as well as reduced apoptosis by 47.1% (p<0.001) and 41.3% (p<0.01), respectively. Finally, honokiol reduced senescence associated ?-galactosidase expression in HFF-1. Honokiol protects both HFF-1 and HaCat against cigarette smoke induced inflammation, collagenolysis, apoptosis, and senescence.