The ErbB family of proteins, structurally related to the epidermal growth factor receptor (EGFR), is found to be overexpressed in many cancers such as gliomas, a lung and cervical carcinomas. Gene therapy allows to modify the expression of genes like ErbB and has been a promising strategy to target oncogenes and tumor suppressor genes. In the current work, novel hydroxyl-rich poly(glycidyl methacrylate) (PGMA)-based cationic glycopolymers were designed for intracellular small interfering RNA (siRNA) delivery to silence the EGFR gene. The cationic polymers with different sugar decoration degrees (0, 9, and 33%) were synthesized by ring-opening reaction of PGMA with ethanolamine and a lactobionic acid-derived aminosaccharide (Lac-NH2). Specific EGFR knockdown of the protein tyrosine kinase ErbB-overexpressing HeLa cells was achieved using these hydroxyl-rich polycation/siRNA complexes. Higher sugar content improved the biocompatibility of the polymers, but it also seems to decrease the EGFR knockdown capability, which should mainly be related to the surface charge of polyplexes. An optimum balance was observed with PGEL-1 (9% sugar content) formulation, achieving similar to 52% knockdown efficiency as well as high cell viability. Considering the specific recognition between galactose residues and asialoglycoprotein receptor in hepatocytes, our novel PGMA-based cationic glycopolymers exhibited promising future to serve as a safe and targeting gene delivery vector to hepatoma cell line like HepG2.