The reported antiandrogenic effects of Spironolactone (Spn) provide a useful approach to be used off-label for treatment of androgenic alopecia (Aga). The aim of this study was to compare the efficiency of niosomes and ethosomes as carriers for the improved skin permeation of Spn. Spn-loaded niosomes and ethosomes were prepared and characterized by transmission electron microscopy, dynamic light scattering, Fourier-transform infrared spectroscopy and differential scanning calorimetry. Additionally, entrapment efficiency and in vitro release % were determined. The selected formulations (N1 and E14) were then incorporated into a hydrox- ypropyl methylcellulose -K4M (HPMC-K4M) gel base (2% w/w) and evaluated for drug permeation and skin deposition using abdominal rabbit skin. Spn-loaded niosomes and ethosomes displayed nanosized spherical morphologies with higher entrapment efficiency for niosomes (95–97.3%) than that for ethosomes (61.5–96.9%). Ex-vivo permeation studies for 24 h demonstrated superior Spn permeation from the ethosomal (Etho) gel (2.17-folds increase) when compared with the niosomal (Nio) gel. In conclusion, Spn can be suc- cessfully prepared as ethosomal gel with acceptable skin permeation and deposition properties which could be a promising new dosage form for off-label use of Spn for further clinical studies on management of Aga.