Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the US. Treatment relies on radiation therapy and chemotherapeutics when surgery is not an option. These treatments have significant negative effects on long-term survival. Previous work in the Rassool laboratory found that combining low, non-cytotoxic doses of poly(ADP-ribose) polymerase (PARP) and DNA-methyltransferase (DNMT) inhibitors increased cytotoxicity in AML and breast cancers. This work highlighted the trapping of both proteins at DNA damage sites, creating cytotoxic double strand breaks (DSBs). We examined this combination in NSCLC and whether low doses of ionizing radiation (IR) would increase treatment efficacy. Introduction of IR with this combination, resulted in decreased cell clonogenicity and increased DSB formation. In vivo testing of this combination with IR showed significantly reduced tumor growth and extended survival rates. This suggests that PARP and DNMT inhibitors in combination with IR could be a novel therapeutic for NSCLC.