Aspirin has recently emerged as an anticancer drug, but its therapeutic effect on lung cancer has been rarely reported, and the mechanism of action is still unclear. Long-term use of celecoxib in large doses causes serious side effects, and it is necessary to explore better ways to achieve curative effects. In this study, we evaluated the synergistic anticancer effects of celecoxib and aspirin in non-small cell lung cancer (NSCLC) cells. In vitro, we evaluated the combined effects of celecoxib (40 μM) and aspirin (8 mM) on cell apoptosis, cell cycle distribution, cell proliferation, cell migration and signaling pathways. Furthermore, the effect of aspirin (100 mg/kg body weight) and celecoxib (50 mg/kg body weight) on the growth of xenograft tumors was explored in vivo. Our data suggest that cancer sensitivity to combined therapy using low concentrations of celecoxib and aspirin was higher than that of celecoxib or aspirin alone. Further research showed that the anti-tumor effect of celecoxib combined with aspirin was mainly produced by activating caspase-9/caspase-3, arresting cell cycle and inhibiting the ERK-MAPK signaling pathway. In addition, celecoxib alone or in combination with aspirin inhibited the migration and invasion of NSCLC cells by inhibiting MMP-9 and MMP-2 activity levels. Moreover, we identified GRP78 as a target protein of aspirin in NSCLC cells. Aspirin induced an endoplasmic reticulum stress response by inhibiting GRP78 activity. Furthermore, combination therapy also exhibited a better inhibitory effect on tumor growth in vivo. Our study provides a rationale for further detailed preclinical and potential clinical studies of the combination of celecoxib and aspirin for NSCLC therapy.