<p>Drug-based ionic systems represent a promising strategy to improve the physicochemical properties and delivery performance of poorly soluble active pharmaceutical ingredients. In this study, ionic derivatives of four nonsteroidal anti-inflammatory drugs (NSAIDs)—ibuprofen, ketoprofen, naproxen, and salicylic acid—were synthesized using three organic cations: didecyldimethylammonium (DDA), 1-ethyl-3-methylimidazolium (EMIM), and cholinium (Chol). The obtained systems were compared with the parent drugs and their sodium salts in terms of thermal stability, viscosity, solubility, lipophilicity, transdermal permeation, and cytotoxicity. Conversion of NSAIDs into ionic forms significantly improved aqueous solubility, increasing from 0.039 to 0.142 g·dm^-3 for the parent drugs to 20.5–178.3 g·dm^-3 for EMIM- and cholinium-based systems, while sodium salts exhibited extremely high solubility (151–232 g·dm^-3). Rheological analysis revealed strong cation-dependent viscosity differences, ranging from approximately 0.2–8.0 Pa·s for EMIM systems to ~ 175 Pa·s for [Chol][KETO] at 20 °C. In vitro permeation studies demonstrated that ionic modification substantially affected transdermal transport. For ibuprofen, cumulative permeation after 24 h increased from 379 µg·cm⁻² (parent drug) to 1629 µg·cm^-2 for [EMIM][IBU] and 1709 µg·cm^-2 for [Chol][IBU]. Naproxen derivatives also showed significant enhancement, reaching ~ 797 µg·cm^-2 for [Na][NAP] and ~ 759 µg·cm^-2 for [EMIM][NAP] compared with 235 µg·cm^-2 for the parent compound. In contrast, DDA-based systems generally reduced permeation. Ketoprofen derivatives exhibited moderate enhancement (up to ~ 1.5-fold), while salicylic acid showed formulation-dependent behaviour. Overall, the results demonstrate that the structure of the organic cation significantly influences the physicochemical properties, skin permeation, and biocompatibility of NSAID-derived ionic systems.</p>