Lung cancer is the primary cause of cancer-related death worldwide. 85%–90% of cases are non-small cell lung cancer (NSCLC) which characteristically exhibits altered epidermal growth factor receptor (EGFR) signaling is a major driver pathway. Unfortunately, therapeutic outcomes in treating NSCLC are compromised by the emergence of drug resistance in response to EGFR-tyrosine kinase inhibitor (TKI) targeted therapy due to the acquired resistance mutation EGFR T790M or activation of alternative pathways. There is current need for a new generation of TKIs to be developed to treat EGFR-TKI-resistant NSCLC. To overcome the above problems and improve clinical efficacy, nanotechnology with targeting abilities and sustained release has been proposed for EGFR-TKI-resistant NSCLC treatment and has already achieved success in in vitro or in vivo models. In this review, we summarize and illustrate representative nano-formulations targeting EGFR-TKI-resistant NSCLC. The described advances may pave the way to better understanding and design of nanocarriers and multifunctional nanosystems for efficient treatment for drug resistant NSCLC. Display omitted •NSCLC patients with EGFR mutation inevitably develop acquired TKIs resistance within one year of treatment.•Advances in nano science have led to development of targeting delivery systems in tumor microenvironment.•These nano-modified therapies show improved in vivo penetration and retention of therapeutic drugs.•A decrease in the side-effect and off targeting through systemic circulation has confirmed.•These nano-modified therapies can provide synergistic anticancer effects and overcome drug resistance in NSCLC.