Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are widely used for pain and inflammation relief, despite their negative gastrointestinal side effects. Various topical formulations of NSAIDs have been developed to mitigate these adverse effects and improve patient compliance. However, their poor aqueous solubility limits their incorporation into hydrophilic gel systems and hinders their permeation through the skin barrier. In this study, we investigated a hydrophobic deep eutectic mixture (HDES) composed of two fatty acids, which significantly enhanced the solubility of an NSAID, Pelubiprofen (PELU) compared to conventional oil phases. The HDES was combined with polyoxyl 40 hydrogenated castor oil (Cremophor RH40^®) and diethylene glycol monoethyl ether (Transcutol HP^®) to prepare microemulsions (MEs) with remarkably small nanodroplet sizes and high drug-loading capacity. In an in vitro permeation test (IVPT) through Strat-M^®, a synthetic membrane with high correlation to human skin, the permeability of PELU in the HDES and MEs group was significantly higher than that of PELU when incorporated with a hydrophilic Carbomer 940 gel. These results suggest the potential fatty acid-based eutectic mixtures in transdermal drug delivery systems.