To integrate photothermal therapy (PTT) with chemotherapy for improved antitumor efficiency, we designed a novel multifunctional composite by attaching Cu x S nanoparticles onto the surface of Y 2 O 3 :Yb/Er hollow spheres through a combined coprecipitation and subsequent hydrothermal route. By altering the initial pH values for the synthesis of precursors, the size and structure properties of the final composites can controllably be tuned. The conjugated folic acid (FA) makes the composite recognize the targeted cancer cells and the attached Cu x S nanoparticles endow the composite with photothermal function. It is found that the release of doxorubicin (DOX) from the functional carrier could be triggered by both pH value and near-infrared (NIR) radiation. In particular, both PTT and chemotherapy can be simultaneously driven by 980 nm laser irradiation. The synergistic therapeutic effect based on PTT and chemotherapy can lead to low in vitro viability of 12.9% and highly strong inhibition of animal H22 tumor in vivo, which is superior to any individual therapy. Moreover, the composite exhibits the clear in vivo red upconversion luminescence (UCL). This multifunctional nanocarrier can be applicable as bioimaging agent and effective antitumor agent for the synergistic interaction between PTT and the enhanced chemotherapy.