Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The high expression of osteopontin (OPN) is an important factor that aggravates drug resistance and causes a poor prognosis in this disease. Therefore, understanding the molecular mechanism of OPN is critical for the treatment and prognosis of NSCLC.We used bioinformatics analysis to verify the expression of OPN in normal lung tissues and lung cancer tissues. Then we overexpressed and knocked down OPN in cell lines to detect cell proliferation, migration, invasion, and effects on signaling pathways. Finally, malignant progression and drug resistance induced by OPN were investigated by the wound healing assay, transwell assay, clone formation assay, and Western blot analysis.We verified that OPN was upregulated in NSCLC tissues, and its overexpression induced NSCLC cell proliferation, migration, and invasion via the mitogen-activated protein kinase (MAPK) pathway. Furthermore, overexpression of OPN reduced the sensitivity of NSCLC cells to cetuximab by upregulating MAPK pathway-related proteins. These results suggested that OPN promoted malignant progression and mediated drug resistance via the MAPK signaling pathway in NSCLC cells.This study reveals the important role of OPN in NSCLC cells, making it a potential target for improving chemotherapy efficiency in patients with NSCLC.