Background <p>Meloxicam is a potent nonsteroidal anti-inflammatory drug (NSAID) utilized for the treatment of acute pain and inflammatory diseases, including osteoarthritis and rheumatoid arthritis. Despite its therapeutic benefits, meloxicam’s oral use can be associated with significant gastrointestinal risks, such as bleeding, ulcerations, and perforations, which pose challenges to patient safety and treatment adherence. Transdermal drug delivery effectively reduces these limitations, with liposomes providing an appropriate system for this route of administration. The study aimed to develop a liposomal formulation of meloxicam that could pass through skin barriers and facilitate transdermal drug delivery.</p> Materials and Methods <p>The study was based on a full factorial design, and the effect of independent variables, namely lecithin, cholesterol, and sonication time, was investigated to determine the liposomes constructed by the thin film hydration method.</p> Results <p>The particle sizes of liposomes ranged from 146 to 268&#xa0;nm, with drug loading percentages between 26.24% and 63.13%. Higuchi’s model best matched the drug release profiles. The findings indicated that reducing the amounts of both lecithin and cholesterol resulted in an increased percentage of drug release. Additionally, enhanced sonication time led to higher steady-state fluxes (Jss) and permeability coefficients, as well as a reduction in lag time (Tlag).</p> Conclusion <p>This study showed that the liposomal formulation improved skin penetration by getting around meloxicam’s physicochemical limitations. This suggests a promising way to deliver the drug topically.</p> Graphical Abstract <p></p>