In this report, uniform LaF3:Ln mesoporous spheres have been synthesized by a facile and mild in situ ionexchange method using yolk-like La(OH)3:Ln mesoporous spheres as templates, which were prepared through a self-produced bubble-template route. It was found that the structures of the final LaF3:Ln can simply be tuned by adding a polyetherimide (PEI) reagent. LaF3:Ln hollow mesoporous spheres (HMSs) and LaF3:Ln flower-like mesoporous spheres (FMSs) were obtained when assisted by PEI and in the absence of PEI. The up-conversion (UC) luminescence results reveal that the doping of Nd3+ ions in LaF3: Ln can markedly influence the UC emissions of the products. It is interesting that an obvious thermal effect is achieved due to the energy back-transfer from Tm3+ to Nd3+ ions under 980 nm near-infrared (NIR) irradiation. The LaF3:Yb/Er/Tm/Nd HMSs show good biocompatibility and sustained doxorubicin (DOX) release properties. In particular, upon 980 nm NIR irradiation, the photothermal effect arising from the Nd3+ doping induces a faster DOX release from the drug release system. Moreover, UC luminescence images of LaF3:Yb/Er/Tm/Nd HMSs uptaken by MCF-7 cells exhibit apparent green emission under 980 nm NIR irradiation. Such a multifunctional carrier combining UC luminescence and hyperthermia with the chemotherapeutic drugs should be of high potential for the simultaneous anti-cancer therapy and cell imaging.