The motility of cancer cells was investigated through the application of migration and wound healing assays. To quantify transcription factor activity, a luciferase reporter assay was conducted. Lung cancer cell metastasis was evaluated using an orthotopic model. Overexpression of CXCL14 and ACKR2 was observed across various lung cancer indicators, including datasets, tissue samples, and cellular lines. Furthermore, the displacement of CXCL14-driven lung cancer cells was determined using both in vitro and in vivo models. In particular, the elimination of ACKR2 completely stopped the motion of cancer cells when stimulated by CXCL14. Concerning ACKR2, it was found to be integral in the CXCL14-triggered signaling cascade that encompasses phospholipase C3 (PLC3), protein kinase C (PKC), and the proto-oncogene c-Src, ultimately escalating nuclear factor-kappa B (NF-κB) transcriptional activity, and driving epithelial-mesenchymal transition (EMT) and the migration of lung cancer cells. These experimental results underscored the significance of the CXCL14/ACKR2 axis in the metastatic process of lung cancer. This research is groundbreaking in revealing CXCL14’s role in the promotion of epithelial-mesenchymal transition (EMT) and metastasis in lung cancer; a previously unknown function. ACKR2, a specific receptor for CXCL14 in lung cancer, is instrumental in mediating CXCL14-induced signaling, leading to cellular mobility. mrtx849 inhibitor Our findings establish a biomarker for predicting the metastasis of lung cancer.