Abstract Cancer-targeting gold/polyacrylamide (Au–PAm) hybrid nanogels were successfully synthesized via water/oil microemulsion polymerization followed by in situ reduction of gold and chemical modification with methotrexate (MTX). The Au nanoparticles range from ∼3 to 7nm and the loading in the hydrogel can be easily controlled. Dynamic light scattering results showed that the hydrodynamic size distribution of these hybrid nanogels is similar to that of blank PAm nanogels (average diameter of ∼30nm), indicating that the Au nanoparticles were mostly incorporated into/onto the nanogels. MTX was used as both a targeting ligand and an anti-cancer drug for chemotherapy. The MTX-functionalized Au–PAm hybrid nanogels (Au–PAm–MTX) at a dosage of 0.5mg/ml or higher can kill KB cells with high efficacy and suppress recovery of the cancer cells. On the other hand, the viability of macrophages showed no obvious decrease after incubation with Au–PAm–MTX, indicating that such materials are not likely to initiate immune responses in the physiological environment and their circulation life time will be prolonged. Hence, such hybrid nanogels can potentially enable safe and effective cancer chemotherapy via targeted co-delivery of cytotoxic Au NPs and MTX in a single carrier to KB cells while avoiding the macrophages.