Epidermal growth factor receptor exon 20 insertion mutations (EGFRex20ins) are a unique molecular subtype of non-small cell lung cancer (NSCLC) linked to resistance to EGFR tyrosine kinase inhibitors of the first and second generations. Until recently, these patients had few and frequently ineffective treatment options. Amivantamab, a bispecific antibody targeting both EGFR and mesenchymal–epithelial transition factor, has become a novel therapeutic strategy for this population. This review explores the mechanism of action of Amivantamab and its clinical efficacy and safety as demonstrated in clinical trials. Additionally, the clinical development of the subcutaneous formulation of amivantamab, real-world evidence and its regulatory status were evaluated. Lastly, we contextualise Amivantamab in the current treatment landscape by contrasting it with mobocertinib and highlighting current studies that aim to improve central nervous system activity and overcome resistance mechanisms. This review highlights the therapeutic benefit of Amivantamab in EGFRex20ins-mutated NSCLC and offers guidance for future research in this quickly developing area.