Development of a delivery system to lower systemic toxicity and enhance doxorubicin (DOX) antitumor efficacy against multi-drug resistant (MDR) tumors is of great clinical significance. Here, lipid/hyaluronic acid (HA)-coated DOX-FeO was characterized to determine its optimal safety and efficacy on a tumor. DOX was first conjugated onto the FeO NPs surface, which was subsequently coated with phosphatidylcholine (PC) lipids, which consisted of a tumor cell-targeting HA ligand, to generate a dual-targeting nanoparticle (NP). DOX-FeO synthesis was validated by the Fourier-transform infrared (FT-IR) analysis results. Core-shell PC/HA@DOX-FeO formation, which had an average particle size of 48.2 nm, was observed based on the transmission electron microscopy (TEM) and dynamic laser light scattering (DLS) results. The saturation magnetization value of PC/HA@DOX-FeO was discovered to be 28 emu/g using vibrating-sample magnetometry. Furthermore, the designed PC/HA@DOX-FeO achieved greater MCF-7/ADR cellular uptake and cytotoxicity as compared with DOX. In addition, PC/HA@DOX-FeO exhibited significant DOX tumor-targeting capabilities and enhanced tumor growth inhibition activity in the xenograft MCF-7/ADR tumor-bearing nude mice following magnetic attraction and ligand-mediated targeting, with less cardiotoxicity. Therefore, PC/HA@DOX-FeO is a potential candidate for MDR tumor chemotherapy. Graphical abstract.