An immunosuppressive effect with drug release control and higher NTPDase activity in the treatment of contact dermatitis was previously reported for a hydrogel containing 0.05% clobetasol propionate-loaded lipid-core nanocapsules (HG-LNC-CP) compared to a hydrogel containing the non-encapsulated drug (HG-CP). In order to investigate the factors underlying this different performance, we evaluated the in vitro skin permeation/penetration of CP from both formulations (HG-LNC-CP and HG-CP). CP did not permeate to the receptor medium during the experiment (24 h), but penetrated into the stratum corneum and viable skin (epidermis and dermis) in significant amounts after 24 h, regardless the type of the formulation. Comparing both formulations, although the relative amount of CP in each skin layer was not affected by the nanoencapsulation, HG-LNC-CP was able to reduce in 5.8, 6.9 and 3.7 times the amount of CP released into the stratum corneum, epidermis and dermis respectively. In this way, the higher effect of HG-LNC-CP previously observed could be due to the controlled drug penetration rate into the skin layers. Moreover, HG-LNC-CP reduces the chances of the corticosteroid to be absorbed systemically as the amount of CP reaching the dermis was reduced. The study reinforces the HG-LNC-CP as a promising dermatological nanomedicine for the treatment of skin disorders.