Abstract: Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) have substantial clinical benefits after treatment with EGFR tyrosine kinase inhibitors (TKIs). However, acquired drug resistance is expected to inevitably develop, and histological transformation to small cell lung cancer (SCLC) is considered a rare mechanism of acquired drug resistance. Considering the wide application and rapid development of next-generation sequencing (NGS), researchers have found that the histological type of EGFR/TP53/RB1 triple mutation in NSCLC is more likely to transform into SCLC after completing targeted therapy. This is particularly worrisome because poor therapeutic efficacy and prognosis are crucial characteristics of transformed SCLC. Thus, in this review, recent studies on the histological transformation of SCLC in patients with EGFR-mutated NSCLC, including those on related transformation mechanisms and novel drugs and treatment strategies, were summarized to provide more potential treatment options for patients with EGFR/TP53/RB1 triple mutation-transformed SCLC.