Colloidal stability of gold nanoparticles (GNPs) is of great importance for their applications. Although a number of ligands have been developed to protect GNPs, irreversible aggregation still happens under some particular conditions. Herein, we report a zwitterionic encapsulation strategy to endow GNPs with ultrastability. Each single GNP is coated with a cross-linked zwitterionic poly(ornithine methacrylamide) hydrogel thin-layer, which prevents particle aggregation under extremely harsh conditions, including lyophilization, strong acid solution, saturated salt solution, and concentrated alkali solution. In addition, the zwitterionic gel layer resists protein adsorption in the biological milieu, keeping the nanoparticles stable in full human blood serum. Furthermore, the amino-acid-derived polymer gel provides numerous conjugation sites for on-demand biomolecular functionalization. With all these merits, the zwitterionic gel coated GNPs hold great potential in many applications such as sensing and theragnostics.