Air pollution is a source of exogenous oxidative stress to which we are daily exposed, leading to a local or even systemic inflammatory status. The chronic exposure to oxidants such as ozone can result in tissue damage including skin conditions. To improve the natural immune defense, counteracting disorders induced by air pollution, natural antioxidants such as mangiferin can be employed. Indeed mangiferin is a natural glucosyl xanthone possessing an antioxidant and anti-inflammatory activity, potentially suitable to prevent skin diseases exacerbation and/or development. In order to find a “green” strategy for transdermal administration of mangiferin, lipid based nanovesicular systems were produced and characterized. Particularly, a formulative study was conducted to design ethosomes. These nanosystems can be considered as a new generation of liposomes, being characterized by a similar composition, while possessing ethanol, able to improve vesicle malleability and cutaneous penetration. The effect of the addition of polysorbate 80 and/or poloxamer 407 to the ethosome composition was investigated on vesicles size distribution and morphology by photon correlation spectroscopy and transmission electron microscopy. To study the capability of ethosome formulations as delivery systems for mangiferin, encapsulation efficiency and in vitro diffusion parameters were evaluated by Franz cells. Mean diameter of vesicles was affected by phosphatidylcholine concentration and by the presence of polysorbate or poloxamer, ranging between 200 and 550 nm. A multilamellar supramolecular structure was detectable in the case of ethosome, in the presence or in the absence of polysorbate or poloxamer. The diffusion kinetic of mangiferin was faster in the case of ethosomes produced in the presence of polysorbate 80. Furthermore, 3D human skin models exposed to ozone enabled to demonstrate the antioxidant and anti-inflammatory effect of mangiferin containing ethosomes against pollutants, especially in the case of vesicles produced in the presence of polysorbate 80, suggesting their possible application to prevent and treat skin conditions associated to oxinflammatory mechanisms.