Multifunctional drug delivery systems combining two or more therapies have a wide-range of potential for high efficacy tumor treatment. Herein, we designed a novel hollow mesoporous Prussian blue nanoparticles (HMPBs)-based platform for targeted and synergetic chemo-photothermal treatment of acute myeloid leukemia (AML). The HMPBs were first loaded with the anticancer drugs daunorubicin (DNR) and cytarabine (AraC), and were subsequently coated with polyethylenimine (PEI) through electrostatic adsorption. Then, zwitterionic sulfobetaine (ZS) and CXCR4 antagonist peptide E5 were modified onto the surface of the nanoparticles via covalent bonding to fabricate a nanoplatform (denoted as HMPBs(DNR + AraC)@PEI-ZS-E5). The nanoplatform showed excellent photothermal effects, superior photothermal stability, reduced nonspecific protein adsorption, efficient targeting capability, a constant hydrodynamic diameter and good biocompatibility. Additionally, a laser-responsive drug release pattern was observed. In vitro results indicated that the nanoplatform could achieve active targeting and remarkable chemo-photothermal synergetic therapeutic effects, showcasing its great potential in AML treatment.