The evaluation of drug percutaneous absorption plays a pivotal role in assessing the efficacy of dermal/transdermal drug delivery systems. Drug therapies rely on biomedical systems capable of precisely regulating drug dosage, controlling the rate of drug release, and mitigating the common side effects associated with many drug delivery formulations. Pluronics are being broadly used as amphiphilic excipients in many drug delivery systems due to their capacity to create supramolecular assemblies in water, exhibiting significant potential for sustained drug delivery. We herein report on the release kinetics of diclofenac sodium contained in novel biocompatible drug delivery systems consisting of aqueous solutions of Pluronic F68. The latter is tested as a release vehicle for percutaneous administration of diclofenac sodium. Its release from Pluronic F68 nanoassemblies in water was experimentally examined by means of a static Franz-type diffusion cell, equipped with a porous membrane simulating the skin absorption, and supported by rheology. Furthermore, the drug release process was modeled through a mass balance for the diclofenac sodium describing its diffusion in pseudostationary conditions through the porous membrane.