Uniform Na5Lu9F32 hollow mesoporous spheres (HMSs) have been successfully prepared by a facile and mild (50 °C for 5 h) coprecipitation process, and Au nanocrystals (NCs) with particle size of about 10 nm were conjugated to poly(ether imide) (PEI) modified HMSs by electrostatic interaction. Compared with Na5Lu9F32:Yb/Er HMSs, the up-conversion (UC) luminescence intensity of Na5Lu9F32:Yb/Er@Au HMSs was much higher under low pump power due to the local field enhancement (LFE) of Au NCs, and there is a surface plasmon resonance (SPR) effect with nonradiative transitions which generates a thermal effect. These two effects have been proved by theoretical discrete-dipole approximation (DDA) simulation. The good biocompatibility of Na5Lu9F32:Yb/Er@Au HMSs indicates them as a promising candidate in the biological field. Particularly, under near-infrared (NIR) laser irradiation, a rapid doxorubicin (DOX) release was achieved due to the thermal effect of Au NCs. In this case, Na5Lu9F32:Yb/Er@Au HMSs exhibit an apparent NIR light-controlled “on/off” drug release pattern. In addition, UC luminescent images uptaken by cells show brighter green and red emission under NIR laser excitation. Therefore, this novel multifunctional (mesoporous, enhanced UC luminescent, and light-triggered drug release) material should be potential as a suitable targeted cancer therapy carrier and bioimaging.