Tacrolimus (TAC) is a drug from natural origin that can be used for topical application to control autoimmune skin diseases such as atopic dermatitis, psoriasis, and vitiligo. Computational simulation based on quantum mechanics theory by solving Schrödinger Equation for n-body problem may allow the theoretical calculation of drug geometry, charge distribution and dipole moment, electronic levels and molecular orbitals, electronic transitions, and vibrational transitions. Additionally, the development of novel nanotechnology-based delivery systems containing TAC can be an approach for reducing the dose applied topically, increasing dermal retention, and reducing the reported side effects due to the controlled release pattern. Firstly, this paper was devoted to obtaining the molecular, electronic, and vibrational data for TAC by using five semi-empirical (SE) methods and one Density Functional Theory (DFT) method in order to expand the knowledge about the drug properties by computational simulation. Then, this study was carried out to prepare TAC-loaded poly(ԑ-caprolactone) nanocapsules by interfacial polymer deposition following solvent displacement and investigate the in vitro drug permeation using the Franz diffusion cell and the photoacoustic spectroscopy. Computational simulations were compared in the three schemes SE/SE, SE/DFT, and DFT/DFT, where the first method represented the procedure used for geometry optimization and the second one was performed to extract electronic and vibrational properties. Computational data showed correspondence with TAC geometry description and electronic properties, with few differences in HOMO - LUMO gap (Δ) and dipole values. The SE/DFT and DFT/DFT methods presented a better drug description for the UV-Vis, Infrared, and Raman spectra with low deviation from experimental values. Franz cell model demonstrated that TAC was more delivered across the Strat-M® membrane from the solution than the drug-loaded poly(ԑ-caprolactone) nanocapsules. Photoacoustic spectroscopy assay revealed that these nanocapsules remained more retained into the Strat-M® membranes, which is desirable for the topical application.