Glycyrrhiza glabra(liquorice) is a widely used medicinal plant for treating inflammatory and respiratory disorders. Its major bioactive compound, glycyrrhetinic acid (GA), exerts anti-inflammatory and immunomodulatory effects through inhibition of 11β-hydroxysteroid dehydrogenase type 2, thereby enhancing local cortisol activity. However, its poor solubility and stability limit its clinical application. In this study, comprehensive metabolite profiling of G. glabraroots using UPLC-HRMS led to the identification of sixty-two metabolites, including triterpene saponins, flavonoids, and phenolic acids. GA was successfully isolated and structurally characterized using NMR and LC-MS/MS techniques. To improve its physicochemical properties, GA was incorporated into β-cyclodextrin-based nano-sponges (NSs), which exhibited nano-sized particles (200–289 nm), low polydispersity, high entrapment efficiency, and stable surface charge. In vitro release studies demonstrated a biphasic sustained-release pattern following Higuchi kinetics under both acidic and physiological conditions. Antioxidant assays revealed that the plant extracts displayed stronger activity than pure GA. In vivo evaluation in rat models of dermal and nasal inflammation showed that GA-loaded NSs significantly reduced inflammatory biomarkers, including ICAM-1, IL-β4, and LTB-4, and markedly improved histopathological features, restoring near-normal tissue architecture without signs of irritation. These findings demonstrate that incorporation of GA into β-cyclodextrin nano-sponges enhances its stability, solubility, and therapeutic efficacy, highlighting its potential as a safe and effective natural treatment strategy for skin and nasal inflammatory disorders.