This study aims to discuss the correlation between miR-1258 and the expression of heparanase (HPSE) in the cancer cells of the patients with non-small cell lung cancer (NSCLC) and the inhibition mechanism of miR-1258 on the invasion of lung cancer cell. The expression level of miR-1258 was detected by TaqMan real-time PCR assay, the expression of HPSE was detected by immunohistochemistry, and the expression level of HPSE in the cancer tissue of each case was detected by western blot and in its adjacent tissue of 53 patients with NSCLC. The influence of miR-1258 on the invasion potential of the lung cancer cell line A549 was studied with lentivirus system including cloned miR-1258 fragments subsequently. The expression of HPSE and miR-1258 in NSCLC tissue was not obviously related to patient's gender, age, differentiation extent of cancer tissue, cancer types, etc., but also staging and lymph node metastasis, and the difference was significant. Further studies showed that the relationship between the expression level of miR-1258 and the expression of HPSE was closer. The relative expression level of miR-1258 was 0.58 ± 0.07 in HPSE positive sample and 1.58 ± 0.11 in HPSE negative sample, and the difference of which was notably significant (P < 0.0001). Western blot showed that the expression level of HPSE was highly negatively related to the expression level of miR-1258. The invasion potential of A549 was notably lowered when transfected by miR-1258. The miR-1258 regulates the expression level of HPSE to influence the morbidity and metastasis of NSCLC. The miR-1258 is likely to become the key to the treatment of lung cancer metastasis.