We report a facile and low-cost approach to design a difunctional nanoplatform (CuS@mSiO2-PEG) as a near-infrared (NIR) light responsive drug delivery system for efficient chemo-photothermal therapy. The nanoplatform demonstrated good biocompatibility and colloidal stability, as well as high loading capacity for the anticancer drug (26.5 wt% for doxorubicin (DOX)). The CuS nanocrystals (core) within these CuS@mSiO2-PEG core-shell nanoparticles can effectively absorb and convert NIR light to fatal heat under NIR light irradiation for photothermal therapy, and the release of DOX from the mesoporous silica (shell) can be triggered by pH and NIR light for chemotherapy. When the CuS@mSiO2-PEG/DOX nanocomposites were irradiated by 980 nm light, both chemotherapy and photothermal therapy were simultaneously driven, resulting in a synergistic effect for killing cancer cells. Importantly, compared with chemotherapy or photothermal treatment alone, the combined therapy significantly improved the therapeutic efficacy.