A new strategy is proposed to synthesize a kind of Au@SiO2 core–shell structure with methotrexate (MTX) loaded within it. Firstly, MTX molecules are attracted to the surface and vicinity of Au nanoparticles (NPs). Then the enriched MTX molecules on the surface of Au NPs have a good chance to be wrapped into the core–shell structure when SiO2 is uniformly deposited on the Au core. Secondly, the effect of Au amount and MTX content on the drug-loading capacity is emphatically studied and the result shows that core–shell structure plays a vital role in drug loading. In addition, the biodegradation process is also examined in phosphate buffer solution (PBS) at 37 °C. The results show that the biodegradation of Au-MTX@SiO2 core–shell structure can be divided into two stages: the release of drug together with the fragmentation of core–shell structure and the subsequent dissolution of SiO2 layers. Lastly, in vitro bioassay tests give the evidence that obvious tumor inhibition can be achieved in presence of Au-MTX@SiO2 NPs even at low concentration and the efficacy can be greatly enhanced by the photothermal therapy on Au cores.