Biofouling generally causes adverse effects to health, such as thrombosis, infection, and pathogenic calcification. Hydrophilic and charge-balanced surface is proved to provide an energy barrier serving as a strong repulsive force against the nonspecific absorption. Unfortunately, the state-ofart technology for silicone modification cannot provide a stable and effective coating for the long-term applications under complex conditions. In this study, we aim to modify the silicone surfaces with a zwitterionic surface ligand to resist nonspecific adsorption of protein, lipid and bacteria. We synthesized a silanized surface ligand conjugated with a head residue of zwitterionic sulfobetaine (SBSi) that bears positively charged quaternary amine and negatively charged sulfonate groups. The bacterial adhesion tests and protein fouling test revealed the excellent antifouling properties of modified silicones. For the real-world application, we modified commercially available silicone hydrogel contact lenses with developed zwitterionic ligands and showed their capability of anti-bacterial adhesion and anti protein fouling. In summary, the strategy of surface engineering in this work can be applied to not only contact lenses but other silicone-based medical devices in facile and effective fashion.