In this study, a versatile tumor-targeted and multi-stimuli-responsive drug delivery vehicle (Se particle@porous silica-folic acid-copper sulfide/doxorubicin (Se@SiO2-FA-CuS/DOX)) was fabricated for combined photothermal therapy with chemotherapy in cancer treatment. Due to excellent targeting ability, the Se@SiO2-FA-CuS/DOX nanocomposites actively accumulated in tumor tissues and thus provided photothermal therapy under NIR irradiation and chemotherapy through the release of DOX and Se. Owing to the synergistic effect of chemotherapy (Se and DOX) and photothermal therapy, the Se@SiO2-FA-CuS/DOX nanocomposites could efficiently inhibit cancer cells both in vitro and in vivo and even completely eliminate tumors. Moreover, as the toxicity of DOX could be reduced by Se, the treatment using Se@SiO2-FA-CuS/DOX nanocomposites exhibited no appreciable adverse reactions. Thus, the Se@SiO2-FA-CuS/DOX nanocomposites have great potential as a multifunctional nanoplatform in future clinical applications.