In bone cancer treatment, local delivery of chemotherapeutic agents is preferred compared to other routes of administration. Delivery of multiple drugs using biodegradable carriers improves the treatment efficiency and overcomes drug resistance and toxicity. With this approach, we have developed multilayer biodegradable core shell nanoparticles (NPs) using the electro-spraying technique to deliver methotrexate (MTX) and doxorubicin (DOX) for the treatment of osteosarcoma. These core-shell NPs with a mean particle size of 212 ± 41 nm consist of hydroxyapatite (HA) and DOX as core with the outer shell made of chitosan (CH) followed by polycaprolactone (PCL) with MTX. The encapsulation efficiency of MTX was around 85% and DOX was 38%. In vitro drug release studies were performed in phosphate buffered saline (PBS) at pH 5 and pH 7.4 for 8 days. Different release profiles were observed in both acidic and alkaline pH. The sequential release of MTX followed by DOX was observed in both pH in sustained manner. Human osteosarcoma MG 63 (OMG-63) cells lines were used to test the cytotoxicity of drug loaded NPs. Multi-drug encapsulated bioresorbable and biodegradable electro-sprayed core shell NPs will be promising as a bone substitute for the treatment of osteosarcoma.