We uncovered that apoptosis induced by treatment with NK‐1R antagonists in CRC cells is mediated by the induction of endoplasmic reticulum (ER) stress via ER calcium release, which results in the inactivation of extracellular signal‐regulated kinase (ERK) signaling and leading to avian myelocytomatosis viral oncogene homolog (c‐Myc) protein degradation, and specifically activation of the protein kinase RNA‐like ER kinase (PERK)‐eukaryotic inition factor 2 (eIF2)α‐ activating transcription factor 4 (ATF4)‐C/EBP‐homologous protein (CHOP) ER stress signaling pathway. Here, EIF2A is linked to colorectal carcinoma.