Non-small-cell lung cancer (NSCLC) is the leading cause of tumor-related death in humans. Radiotherapy is a crucial strategy for NSCLC treatment, although its effectiveness is limited by the radio-resistance of tumor cells. Our current research finds that the protein arginine methyltransferase 7 (PRMT7) is upregulated in NSCLC and correlates with poor prognosis. Pharmacological inhibition of PRMT7 by SGC3027, a specific small-molecule PRMT7 inhibitor, suppresses the proliferation, migration and invasion of NSCLC. Combining irradiation with SGC3027 strengthens the impact of irradiation on the biological behaviors of NSCLC cells. We also find that SGC3027 specifically activates ATM kinase and its downstream cell cycle checkpoint kinases to enhance radiobiological response in NSCLC. These findings underscore the promising therapeutic potential of PRMT7 inhibitors as well as combining PRMT7 inhibition with irradiation exposure for effective NSCLC therapies.