In this study, a hybrid dual drug-loaded hydroxyapatite-oxidized dextran methacrylate core-shell nanocarrier was formulated and explored for combinatorial delivery of doxorubicin (DOX) and methotrexate (MTX) to bone cancer. The synthesized nanocarrier was well characterized by different techniques. In vitro drug release studies in both acidic (pH 5) and alkaline (pH 7.4) conditions showed sequential release of MTX followed by DOX in a sustained manner for 10 days. Biocompatibility and cytotoxicity studies performed using drug-loaded nanoparticles (NPs) on fibroblast L929 cells and osteosarcoma MG63 cells (OMG63) showed that the NPs were highly biocompatible and showed concentration-dependent toxicity. Gene expression studies in OMG-63 cells exhibited the upregulation of caspase-3 and BAX which confirmed the apoptosis induced by dual drug-loaded NPs. The nanocarrier is expected to be a potential bone void filling material, as well as a platform for sequential delivery of DOX and MTX for the treatment of bone cancer. Copyright © Materials Research Society 2020.