Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), including cetuximab and panitumumab, have been used in clinic settings to treat cancer. They have also recently been applied to antibody–drug conjugates (ADCs); however, their clinical efficacy is limited by several issues, including lower internalization efficiency. The binding of cetuximab to the extracellular domain of EGFR suppresses ligand-induced events; therefore, we focus on ligand-independent non-canonical EGFR endocytosis for the delivery of ADCs into cells. Tumor necrosis factor-α (TNF-α) strongly induces the endocytosis of the cetuximab-EGFR complex within 15 min via the p38 phosphorylation of EGFR in a tyrosine kinase-independent manner. A secondary antibody conjugated with saporin, a ribosome-inactivating protein, also undergoes internalization with the complex and enhances its anti-proliferative activity. Anti-cancer agents, including cisplatin and temozolomide, also induce the p38-mediated internalization. The results of the present study demonstrate that synchronous non-canonical EGFR endocytosis may be a feasible strategy for promoting the therapeutic efficacy of EGFR-targeting ADCs in clinical settings.