In the present research work, we addressed the changes in skin by which deep eutectic solvents (DES) enhanced transdermal permeation of bioactive compounds and propose a rationale for this mechanism. Several studies showed that these unusual liquids were ideal solvents for transdermal delivery of biomolecules, but to date, no histological studies relating the action of DES to changes in the structure of the outer skin barrier have been reported. In the research effort described herein, we presented an in-depth analysis of the changes induced in the skin by choline geranate DES, a compound with proven capabilities of enhancing transdermal permeation without deleterious impacts on the cells. The results obtained showed that a low percentage of DES acted as a transient disruptor of the skin structure, facilitating the passage of bioactive compounds dissolved in it.