Background <p>Oxidative stress and inflammation are central to the pathogenesis of numerous diseases, including skin disorders, arthritis, and neurodegenerative conditions. UV-induced skin damage is largely attributed to the generation of reactive oxygen species (ROS), leading to oxidative stress, inflammation, and melanogenesis. <i>Oxalis corniculata</i>, a traditional medicinal herb rich in polyphenolic compounds such as syringic acid, exhibits notable antioxidant and anti-inflammatory activities. However, its therapeutic efficacy is limited by poor bioavailability.</p> Aim and Objective <p>This study aimed to develop, characterize, and evaluate a phytosomal delivery system of O. corniculata to enhance its biological efficacy. Additionally, a robust High-Performance Thin-Layer Chromatography (HPTLC) method was developed and validated for the quantification of syringic acid using an Analytical Quality by Design approach.</p> Methods <p>Phytosomes were prepared using phosphatidylcholine via the thin-film hydration method and evaluated for particle size, zeta potential, entrapment efficiency, and yield. A DoE-optimized HPTLC method using toluene: ethyl acetate: formic acid (7.5:2.5:0.5, v/v/v) was validated. Biological evaluation included in vitro antioxidant, anti-inflammatory, and UV protection assays. Molecular docking of syringic acid was performed against key protein targets (1N8Q, 1XKK), showing strong binding affinities (–6.4 and –6.1 kcal/mol, respectively), supporting its therapeutic potential.</p> Results <p>F5 was the optimized formulation with superior characteristics. The phytosome exhibited enhanced biological activities compared to the extract. SPF values improved significantly upon phytosomal encapsulation.</p> Conclusion <p>The integration of molecular docking, AQbD-based HPTLC quantification, and phytosomal delivery significantly enhanced the bioefficacy of syringic acid, supporting its potential in managing oxidative stress-induced skin disorders.</p> Graphical Abstract <p></p>