Objective <p>Lornoxicam (LOR) is a potent NSAID with poor solubility, short half-life, and significant gastric side effects, which limit its oral use, necessitate frequent dosing and reduce patient compliance. This study aimed to develop and optimize a transethosomal formulation of LOR for transdermal delivery due to its favourable skin permeation properties.</p> Methods <p>A Box-Behnken design was used to optimize LOR-loaded transethosomes. The effect of selected independent variables (lecithin, Span 80, and ethanol concentrations) was studied regarding the drug entrapment efficiency and the amount of drugpermeatedafter6h. A transethosomal gel was prepared by incorporating the optimized formulation into a Carbopol gel base and was further characterized.</p> Results <p>The optimized formulation was further characterized for vesicle size, PDI, zeta potential, FTIR, DSC/TGA, XRD, and drug release kinetics. A transethosomal gel was prepared by incorporating the optimized formulation into a Carbopol gel base and was further characterized for pH, viscosity, drug content, ex vivo and in vivo anti-inflammatory properties, irritation, and stability studies. The LOR-loaded transethosomes containing 4% lipid, 32.5% ethanol, and 16.88% Span 80 fulfilled the criteria for an ideal formulation. The entrapment efficiency and the amount of drug permeated after 6 h of the optimized formulation were 92.1% and 85.4%, respectively. Characterization verified stable, nano-sized vesicles with a particle size of 527.2 nm, PDI of 0.429 and a zeta potential of -34.1 mV. Ex-vivo study demonstrated the increased skin permeation from the transethosomal gel. Stability tests proved the physical stability of the transethosomal gel over the period of 60 days.</p> Conclusions <p>Based on data obtained the present study showed that transethosomes could be a potential drug carrier for the transdermal application of the LOR.</p> Graphical Abstract <p></p>