Histidine triad nucleotide binding protein 2 (HINT2) belongs to a HIT superfamily. It is ubiquitous and can be detectedin all forms of life. Recently, this protein has been reported to function as a tumor suppressor in some kind of cancers. However, little is known about its precise role in non-small cell lung cancer (NSCLC). In the present study, we explored the effects of HINT2 on the invasive potential of NSCLC cells. Our results showed that the expression of HINT2 was reduced in NSCLC tissues and cell lines. Up-regulation of HINT2 inhibited NSCLC cell invasion in vitro and tumor metastasis in vivo. We also found that the inhibitory effect of HINT2 on NSCLC cell invasion was associated with reduction of COX-2 expression. In addition, our further investigation on the underlying mechanisms demonstrated that up-regulation of HINT2 inhibited NSCLC cell invasion via COX-2/PGE₂-mediated activation of ß-catenin signaling. In conclusion, we presented evidence that HINT2 exerted a tumor-suppression effect on the progression of NSCLC. Thus, HINT2 might be a promising molecular target for treatment of NSCLC.