Drug resistance is a major challenge for the clinical application of chemotherapeutic drugs. In this study, a nanoparticle system containing hyaluronic acid (HA) shell and poly(β-amino) ester (PBAE) core was designed as a carrier for doxorubicin (DOX), a commonly used chemotherapeutic drug in clinical, to overcome the drug resistance in breast cancer cells. DOX-loaded PBAE (PBAE/DOX) nanoparticles were firstly prepared using the O/W emulsion solvent evaporation method, and followed by the surface coating of HA via charge interaction. HA-coated PBAE/DOX (HA/PBAE/DOX) nanoparticles had a classic “core–shell” structure with a size of 185.0 nm and displayed obvious pH-responsive in vitro drug release property. Compared to free DOX and PBAE/DOX nanoparticles, HA/PBAE/DOX nanoparticles exhibited the enhanced cytotoxicity, cell apoptosis and S-phase cell cycle arrest in drug-resistant human breast cancer MCF-7/ADR cells, in which P-glycoprotein (P-gp), a typical and well-known mediator of cancer drug resistance, and CD44, a cell-surface adhesion receptor, were over-expressed. As HA was a natural ligand for CD44, HA/PBAE/DOX nanoparticles could enter MCF-7/ADR cells via CD44-mediated endocytosis, thus efficiently avoided the efflux effect of P-gp and improved the cellular accumulation of DOX. In summary, HA/PBAE nanoparticle system could be used as a potential carrier of chemotherapeutic drugs for the reversal of drug resistance in cancers.