The ability to selectively destroy cancer cells while sparing normal tissue is highly desirable during cancer therapy. Herein, dual-targeted photothermal therapy was achieved by the integration of upconversion nanoparticles, Fe3O4 nanoparticles (IONPs), Prussian blue nanoparticles (PBNPs) and hyaluronic acid (HA). PBNPs converted near-infrared (NIR) light into heat and HA/Fe3O4 NPs served as dual-targeting moieties. The as-obtained nanocomposites could also be applied as a multimodal probe for upconversion luminescence (UCL) imaging, enhanced T2-weighted magnetic resonance (MR) imaging and photoacoustic tomography (PAT) imaging. This multifunctional nanoparticle (MFNP) system prepared by a layer-by-layer (LBL) assembly method exhibited excellent dispersivity and low toxicity in vitro and in vivo. Furthermore, the research provided effective results for dual-targeted photothermal ablation of cancer with ∼4 fold higher tumor accumulation than that in the absence of HA/magnetic field. The photothermal therapeutic efficacy has been greatly improved in the S180 tumor model. We present a strategy for multimodal imaging-guided, dual-targeted physical cancer therapy and highlight the promise of using multifunctional nanostructures for cancer theranostics.