Diclofenac-loaded phospholipid vesicles, namely conventional liposomes, ethosomes and PEVs (penetration enhancer-containing vesicles) were developed and their efficacy in TPA (phorbol ester) induced skin inflammation was examined. Vesicles were made from a cheap and unpurified mixture of phospholipids and diclofenac sodium; Transcutol P and propylene glycol were added to obtain PEVs, and ethanol to produce ethosomes. The structure and lamellar organization of the vesicle bilayer were investigated by transmission electron microscopy and small and wide angle X-ray scattering, as well as the main physico-chemical features. The formulations, along with a diclofenac solution and commercial Voltaren Emulgel, were tested in a comparative trial for anti-inflammatory efficacy on TPA-treated mice dorsal skin. Vesicles were around 100 nm, negatively charged, able to encapsulate diclofenac in good yields, and disclosed different lamellarity, as a function of the formulation composition. Vesicular formulations promoted drug accumulation and reduced the permeation. Administration of vesicular diclofenac on TPA-inflamed skin resulted in marked attenuation of oedema and leucocyte infiltration, especially using PEVs. Histology confirmed the effectiveness of vesicles, since they provided an amelioration of the tissual damage induced by TPA. The proposed approach based on vesicular nanocarriers may hold promising therapeutic value for treating a variety of inflammatory skin disorders.