<p>The present study aimed to develop and characterize a nanostructured lipid carrier (NLCs)-based topical gel of Tofacitinib for the treatment of psoriasis, with both in vitro and in vivo characterization. The NLCs were prepared using the ultrasonication and homogenization method and analyzed for particle size, polydispersity index, zeta potential, drug entrapment efficiency, drug loading, surface morphology (via SEM), thermal properties (DSC, TGA), chemical characterization (FTIR), and in vitro cytotoxicity against the A375 cell line. The optimized NLCs were incorporated into a Carbopol 940 gel and evaluated for drug content, rheological behavior, texture profile, in vitro drug release, ex vivo skin permeation, biochemical, and histopathological effects. The NLCs appeared as spherical nanostructures with a narrow size distribution, within the nanometric range. The formulations demonstrated significant skin permeation within the epidermal and dermal layers. Histopathological examination of skin samples confirmed the formulation’s effectiveness in treating psoriasis. The NLC-based gel demonstrated potential as a drug delivery system, increasing the percutaneous penetration of Tofacitinib and reducing inflammation and erythema, thereby enhancing psoriasis treatment.</p> Graphical Abstract <p></p>