Hepatocellular carcinoma (HCC), the most common primary liver cancer, faces treatment challenges due to drug resistance and poor bioavailability, with sorafenib, a key therapy, characterized by rapid clearance and significant side effects. This paper describes the development of amphiphilic graft copolymers for efficient loading and delivery of sorafenib through controlled Atom Transfer Radical Polymerization (ATRP). The amphiphilic graft copolymer PHEA-g-IB-(pButMA)-g-PEG-Bt was synthesized to enhance tumor specificity via biotin-mediated targeting. The synthesis involved a three-step process, with successful functionalization confirmed through NMR and Size Exclusion Chromatography (SEC) analyses. Sorafenib-loaded nanoparticles, prepared via dialysis-based nanoprecipitation, exhibited a mean size of ∼ 300 nm, suitable for oral and parenteral administration, while drug release studies confirmed a sustained release profile, minimizing premature systemic loss and reducing the need for frequent administration. Evaluation of cytocompatibility and anticancer efficacy tested in vitro on HepG2 and HuH-7 cell lines revealed that biotinylated sorafenib-loaded nanoparticles had the highest ability to reduce cell viability. The enhanced anticancer effect of biotinylated NPs was validated in vivo using a murine tumor xenograft model, as evidenced by reduced tumor growth, lower Ki-67 proliferation index, and diminished CD31-positive vasculature. Protein expression analysis demonstrated that PBB-Bt@SOR elicited the strongest activation of p-p38 MAPK and caspase-8-mediated apoptosis, while enhancing the expression of the pro-survival AKT pathway. Overall, the study confirms that biotinylated sorafenib-loaded nanoparticles improve tumor suppression in HCC models, demonstrating their effectiveness in targeted drug delivery. These findings suggest biotin decorated polyamino aspartamide-based nanoparticles as a promising strategy to optimize chemotherapy regimens, minimizing systemic toxicity in HCC treatment.