Leptin acts on energy metabolism and plays a role in skin repair and in the modulation of cellular redox balance as well. Here, we investigated the effects of leptin on the redox homeostasis in keratinocytes, by evaluating reactive oxygen species (ROS) generation, glutathione content, antioxidant enzymes, activating protein 1 (AP-1) activity, and expression of AP-1-dependent, differentiation-specific genes. We also evaluated the systems involved in the maintenance of a positive ascorbate/dehydroascorbate ratio, i.e., transport and recycling. Leptin altered the keratinocyte redox state, as evident by enhanced ROS generation, oxidized/reduced glutathione ratio, and AP-1 activity. Still, this phenomenon was temporary. Indeed, we found an adaptive response, as demonstrated by an early induction of catalase and a late induction of specific dehydroascorbate reductase activities. In particular, leptin-treated cells showed an increased ability to reduce dehydroascorbate, both in a NADH, lipoic acid- and in a NADPH, thioredoxin-dependent manner. Our results show that leptin may induce adaptation to oxidative stress in skin, leading to an improved vitamin C homeostasis.