<p>Silibinin, a natural flavanone extracted from the milk thistle plant (<i>Silybum marianum</i>), has been shown to have various therapeutic applications, including liver protection, antioxidant, anticancer, anti-inflammatory, and many other effects. However, silibinin exhibits poor oral absorbance and low bioavailability owing to its limited water solubility, which limits its therapeutic efficiency and further clinical translation. To address these issues, we propose an antioxidant glycopolypeptide micelle strategy to target the delivery of silibinin to enhance its solubility, bioavailability, and antioxidant activity. This versatile micelle self-assembled from a glycopolypeptide, <i>N</i>-acetylgalactosamine-grafted poly(glutamic acid)-<i>block</i>-poly(tyrosine). <i>N</i>-acetylgalactosamine (GalNAc) is incorporated to enable liver targeting by selectively binding to the asialoglycoprotein receptor, which is overexpressed on hepatocellular carcinoma cells. The antioxidant polypeptide polytyrosine, as well as encapsulated silibinin, exhibits a synergistic reactive oxygen species (ROS) scavenging effect. The obtained results confirmed that silibinin can be effectively encapsulated into the glycopolypeptide micelles through self-assembly, achieving a loading efficiency and loading content of 96.6% and 42.9%, respectively. The silibinin-loaded glycopolypeptide micelles exhibited enhanced cellular uptake and a synergistic ROS scavenging effect in hepatocellular carcinoma cells. Overall, these antioxidant glycopolypeptide micelles hold promise as safe and efficient drug delivery systems for targeting hepatocellular carcinoma cells, potentially providing an effective strategy to enhance the bioavailability and antioxidant activity of silibinin.</p>