Targeting controlled release core–shell nanocarriers with the potential to overcome multidrug resistant (MDR) lung cancer were prepared based on demethoxycurcumin (DMC) loaded amphiphilic chitosan nanoparticles coated with an anti-EGFR antibody layer. The nanocarriers were characterized with regard to size with dynamic light scattering, SEM, and TEM. The characterization confirmed the nanocarriers to have a surface coating of the anti-EGFR antibody and a final size excellently suited for circulating targeting nanocarriers, i.e., <200 nm in diameter. In vitro drug release revealed extended quasi-Fickian release from the nanocarriers, with the anti-EGFR layer further reducing the release rate. Cell culture experiments using normoxic and MDR hypoxic cells overexpressing EGFR confirmed improved DMC delivery for anti-EGFR coated particles and revealed that the DMC was delivered to the cytoplasmic region of the cells, forming nanoprecipitates in lysosomes and endosomes. The effective endocytosis and targeting of the core–shell nanoparticles resulted in the nanocarriers achieving high cytotoxicity also against MDR cells. The therapeutic potential was further confirmed in an A549 xenograft lung tumor mouse model, where DMC loaded core–shell nanocarriers achieved about 8-fold reduction in tumor volume compared with control group over the 8 weeks of the investigation. Both in vitro and in vivo data suggest the anti-EGFR coated core–shell nanocarriers as highly promising for treatment of hypoxic MDR cancers, especially for non-small cell lung cancer.