Designing a single multifunctional nanoparticle that can simultaneously impart both diagnostic and therapeutic functions is considered to be a long-lasting hurdle for biomedical researchers. Conventionally, a multifunctional nanoparticle can be constructed by integrating organic dyes/magnetic nanoparticles to impart diagnostic functions and anticancer drugs/photosensitizers to achieve therapeutic outcomes. These multicomponents systems usually suffer from severe photobleaching problems and cannot be activated by near-infrared (NIR) light. Here, it is demonstrated that all-in-one lanthanide-doped mesoporous silica frameworks (EuGdOx@MSF) loaded with an anticancer drug, doxorubicin (DOX) can facilitate simultaneous bimodal magnetic resonance (MR) imaging with approximately twofold higher T1-MR contrast as compared to the commercial Gd(III)-DTPA complex and fluorescence imaging with excellent photostability. Upon a very low dose (130 mW cm−2) of NIR light (980 nm) irradiation, the EuGdOx@MSF not only can sensitize formation of singlet oxygen (1O2) by itself but also can phototrigger the release of the DOX payload effectively to exert combined chemo-photodynamic therapeutic (PDT) effects and destroy solid tumors in mice completely. It is also discovered for the first time that the EuGdOx@MSF-mediated PDT effect can suppress the level of the key drug resistant protein, i.e., p-glycoprotein (p-gp) and help alleviate the drug resistant problem commonly associated with many cancers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim