Abstract: The epidermal growth factor receptor (EGFR) is a key oncogenic driver in non-small cell lung cancer (NSCLC), and its mutations have significant clinical implications. While classical mutations, such as exon 19 deletions and exon 21 L858R substitutions, are well established, increasing attention has shifted toward less common, non-classical EGFR mutation subtypes. The widespread adoption of high-throughput sequencing technologies such as next-generation sequencing (NGS) has substantially improved the detection rate of non-classical EGFR mutations. Thus, their molecular characteristics and therapeutic responses have been increasingly elucidated. However, due to their significant heterogeneity, substantial variability exists in the sensitivity of different non-classical mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Furthermore, the scarcity of clinical samples limits the availability of robust evidence. Additionally, prolonged clinical use of EGFR-TKIs can also lead to acquired resistance, further complicating treatment strategies. Despite these challenges, ongoing research continues to explore targeted therapies for patients with non-classical EGFR mutations. This review summarizes recent studies on non-classical EGFR mutations in NSCLC, examines current therapeutic approaches, and outlines clinical recommendations for managing patients after EGFR-TKI treatment failure. By integrating existing evidence and clinical experience, this review aims to optimize individualized treatment strategies for these patients, with the ultimate goal of improving their prognosis and quality of life.