Purpose <p>We aimed to evaluate the anti-inflammatory activities of <i>Zanthoxylum piperitum</i> leaves extract and its liposomal formulation which can potentially substitute.</p> Methods <p>ZanW, a water-soluble extract, was prepared via ethanol and aqueous extraction. Subsequently, lipopolysaccharide (LPS) was utilized as a stimulus to induce inflammation in Raw264.7 cells, aiming to confirm the anti-inflammatory effects. For enhanced delivery, liposomal ZanW was prepared via the thin-film hydration method and characterized for particle size and encapsulation efficiency. Franz diffusion cell assay assessed the enhanced mucosal permeability of the liposomal formulation. Rhinitis/sinusitis were induced in mice using Ovalbumin (OVA) respectively. Utilizing animal models, we assessed the efficacy of improving inflammatory conditions using various methods.</p> Results <p>ZanW, which contains flavonoids such as quercitrin, afzelin, and hyperoside, exhibits antioxidant activity that reduces inflammation by decreasing oxidative stress. ZanW inhibits the AKT and NF-κB/IκB pathway and suppresses the generation of COX-2, PGE2, and NO. Using a rhinitis/sinusitis model, improvements were observed in symptoms associated with diseases. ZanW was found to reduce the production of cytokines associated with allergic inflammation. Furthermore, liposomal formulation of ZanW was shown to enhance mucosal permeability and retention time, as confirmed by Franz cell diffusion assays. The liposome encapsulated ZanW exhibited superior diffusion across the artificial membrane compared to non-formulated ZanW, supporting the potential of this delivery system for improved intranasal efficacy.</p> Conclusion <p>In summary, ZanW exhibited potent anti-inflammatory effects in vitro and in vivo, its liposomal formulation improved mucosal delivery, supporting its potential as a natural, intranasal therapy for allergic inflammation.</p>