Stobadine is a model drug with pyridoindole structure with cardioprotective and antioxidant properties. Permeation properties of its acyl derivatives were studied to find a proper prodrug form. The experimental study of transdermal delivery of derivatives was combined with the theoretical approach in which the partition coefficients of substances were estimated by means of fragmentation or quantum chemical calculations. All modes applied showed differences in the transport properties of derivative S1 (N-acetyl stobadine). The experimental results obtained for the flux of S1 were higher by one order of magnitude than for the other derivatives and the parent drug. The results are discussed from the point of view of physicochemical properties of derivatives. We concluded that the exceptional permeation value of S1 derivative results from the concurrence of partitioning coefficient, dissociation constant, and arrangement of permeation set.