Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-Tkis) represented by osimertinib have become the first-line standard treatment option for EGFR-mutated non-small cell lung cancer (NSCLC), significantly improving progression-free survival and overall survival in patients. However, almost all patients eventually develop acquired resistance, which severely limits the long-term efficacy. This article systematically reviews the main molecular mechanisms of resistance to third-generation EGFR-Tkis and the latest research progress. Existing evidence suggests that resistance mechanisms can be roughly divided into two major categories: EGFR-dependent (on-target) and EGFR-independent (off-target). EGFR-dependent resistance mainly includes secondary mutations such as C797S, mutations in other kinase domains, and EGFR gene amplification, which directly affect drug binding to the target. Egfr-independent resistance is more complex, involving bypass signaling pathway activation (such as MET amplification, HER2 or AXL abnormalities), histological transformation (such as adenocarcinoma to small cell lung cancer transformation), downstream signaling pathway abnormalities (RAS/MAPK, PI3K/AKT pathways), and cell cycle regulation imbalance. In addition, recent studies have further revealed the important roles of metabolic reprogramming, epigenetic regulation, tumor-microenvironment interactions, and drug-resistant persistent cells in the formation of resistance. In terms of therapeutic strategies, novel approaches such as combined targeted therapy for resistance mechanisms, next-generation EGFR inhibitors, bispecific antibodies, antibody-drug conjugations, immunotherapy and cell therapy are advancing and showing good clinical prospects in some patients. Overall, third-generation EGFR-TKI resistance shows high heterogeneity and dynamic evolution characteristics, and in the future, multi-omics detection, dynamic molecular monitoring, and individualized combination therapy strategies will be needed to achieve more precise and durable disease control.