Lung adenocarcinoma (LUAD) is a highly prevalent and lethal malignant tumor, with the aberrantly activated EGFR signaling pathway playing a crucial role in its development. However, resistance to tyrosine-kinase inhibitors (TKIs) targeting EGFR significantly limits the efficacy of LUAD clinical therapy. Therefore, it is imperative to identify novel therapeutic targets and elucidate the regulatory mechanisms of EGFR for improving LUAD treatment outcomes. In this study, we discover that DNAJC5 functions as an oncogene in LUAD. We observe elevated protein levels of DNAJC5 in tissues from LUAD patients, which are strongly associated with poor prognosis among these individuals. Furthermore, overexpression of DNAJC5 promotes proliferation and migration of LUAD cells both in vitro and in vivo. Mechanistic investigations reveal that DNAJC5 interacts with the intracellular domain of EGFR and enhances its endocytosis and recycle, thereby augmenting EGFR activity and downstream signaling pathways. Additionally, we find that DNAJC5 binds to AP2A1 protein-a key player in EGFR endocytosis-and strengthens its interaction with EGFR. Knockdown experiments targeting AP2A1 attenuate the ability of DNAJC5 to promote proliferation and migration of LUAD cells. Collectively, our findings unveil a functional role for DNAJC5 in regulating EGFR trafficking and driving LUAD progression.