Ultradeformable liposomes were formulated using naringin (NA), a flavanone glycoside, at different concentrations (3,6 and 9 mg/mL). Nanovesicles were small size (∼100 nm), regardless of the NA concentration used, and monodisperse (PI < 0.30). All formulations showed a high entrapment efficiency (∼88%) and a highly negative zeta potential (around −30 mV). The selected formulations were highly biocompatible as confirmed by in vitro studies using 3T3 fibroblasts. In vitro assay showed that the amounts (%) of NA accumulated in the epidermis (∼10%) could explain the anti-inflammatory properties of ultradeformable liposomes. In vivo studies confirmed the higher effectiveness of ultradeformable liposomes respect to betamethasone cream and NA dispersion in reducing skin inflammation in mice. Overall, it can conclude that NA ultradeformable liposomes can be considered as a promising formulation for the treatment of skin inflammatory diseases.