Inflammatory skin diseases, such as atopic dermatitis and psoriasis, can significantly impact patients' quality of life due to symptoms caused by an overactive immune response. Clobetasol, a potent corticosteroid, is commonly used to relieve these symptoms by reducing inflammation and suppressing immune responses. However, prolonged use can lead to adverse effects, including skin atrophy, hypopigmentation, and Cushing-like syndrome. To tackle these issues, nanotechnology has been extensively used to enhance drug strength, stability, and controlled release, improving therapeutic efficacy and safety. In this study, clobetasol-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles were developed and incorporated into a thermosensitive hydrogel for topical treatment of inflammatory skin diseases. Nanoparticles were prepared by nanoprecipitation using PLGA (polymer), polyvinyl alcohol (PVA, stabilizer), acetone (solvent), and clobetasol (drug). Particle size, polydispersity index (PDI), and zeta potential (ZP) were determined using a Zetasizer Nano ZS. Optimized nanoparticles for topical drug absorption exhibited an average size of 232 ± 20 nm, PDI of 0.18 ± 0.06, and a slightly negative surface charge (-6.94 ± 2.55 mV), consistent with PLGA’s ester terminals. Thermosensitive hydrogels were successfully formulated using the cold method for nanoparticle incorporation, displaying a gelation temperature (32.33 ± 0.58°C) identical to skin temperature. In vitro studies revealed controlled release of clobetasol from the nanoparticles and the hydrogel incorporated with the nanoparticles, with the latter showing a lower cumulative percentage. Therefore, both formulations offer a promising therapeutic approach for treating inflammatory skin diseases, minimizing clobetasol-related side effects through controlled release.