Recently, incorporating multiple components into one nanostructured matrix to construct a multifunctional nanomedical platform has attracted more and more attention for simultaneous anticancer diagnosis and therapy. Herein, a novel anti-cancer nanoplatform has been successfully developed by coating a uniform shell of poly(acrylic acid) (PAA) on the surface of CuS-decorated upconversion nanoparticles (UCNPs). Benefiting from the enhanced 808 nm-excited UCL intensity of the multilayer UCNPs, the unique photothermal properties of CuS and the pH-responsive drug release capacity of the PAA shell, such a nanoplatform design of UCNPs-CuS@PAA (labeled UCP) offers a new route to achieve 808 nm-excited UCL imaging guided chemo/photothermal combination therapy. We have found that the combined chemo/photothermal therapy can significantly improve the therapeutic efficacy compared with chemotherapy or photothermal therapy (PTT) alone. Moreover, the pH/NIR-dependent drug delivery properties, 808 nm-excited UCL imaging, as well as in vitro/in vivo biocompatibility tests were also investigated in detail. These results show promising applications of UCP nanoparticles as a novel theranostic agent for the detection and treatment of tumors.