Abstract: Curcumin (CUR), an acidic polyphenolic natural compound extracted from plants of the Zingiberaceae family, exhibits remarkable pharmacological activities such as anti-inflammatory and antioxidant effects. However, its strong hydrophobicity, poor membrane permeability, and low bioavailability severely limit its therapeutic application. In this study, glycyrrhizic acid (GA), a natural compound with surfactant properties, was employed as a carrier to construct curcumin-glycyrrhizic acid self-assembled micelles (CUR-GMS) in order to enhance the solubility and bioavailability of CUR and improve its therapeutic efficacy against ulcerative colitis (UC). Molecular dynamics simulations confirmed that GA and CUR spontaneously formed core-shell structured micelle via hydrophobic interactions and hydrogen bonding, providing theoretical evidence for the feasibility of self-assembly. CUR-GMS were prepared via the thin-film dispersion method and characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The micelles exhibited a spherical morphology with a particle size of 46.33 ± 0.63 nm, a zeta potential of 59.76 ± 2.54 mV, an encapsulation efficiency of (98.82 ± 0.41)%, and a drug-loading capacity of (28.24 ± 0.11)%. CUR and GA were present in an amorphous state within the micelles. Compared with the raw drug, CUR solubility was markedly improved; the cumulative in vitro release within 48 h was increased by 2.33 to 3.98-fold, and oral bioavailability was enhanced by 6.36-fold. In vivo pharmacodynamic studies demonstrated that CUR-GMS significantly alleviated symptoms of dextran sulfate sodium (DSS)-induced UC in mice, with the underlying mechanism potentially related to the regulation of macrophage polarization. In conclusion, CUR-GMS constructed with GA significantly improved the oral bioavailability of CUR and enhanced its therapeutic efficacy against UC. All animal experiments were approved by the Ethics Committee of the Animal Experimentation Science and Technology Center, Jiangxi University of Chinese Medicine (No: JZLLSC20230350).