Lung cancer remains the leading cause of cancer-related death worldwide. Previous studies have shown that the novel KIAA0247 gene potentially targeted by the tumor suppressor p53 may inhibit the development of several cancers. However, the exact function of KIAA0247 in non-small-cell lung cancer (NSCLC) is unknown. The purpose of the present study was to clarify the role of KIAA0247 in NSCLC. KIAA0247 expression was evaluated in tumors and adjacent normal tissues of 197 NSCLC patients by immunohistochemistry and real-time PCR and analyzed for association with clinicopathological parameters. Results indicated that KIAA0247 levels positively correlated with cell differentiation (P < .001) and patient survival (P < .0001) and negatively correlated with lymph node metastasis (P < .001) and advanced p-TNM stage (P < .001). In cultured NSCLC cell lines, KIAA0247 overexpression inhibited cell migration, invasion, and proliferation and downregulated the expression of Jagged1, Notch1 intracellular domain (NICD), Snail, cyclin D1, RhoA, RhoC, and MMP9, while upregulating that of E-cadherin and p21. The Notch inhibitor DAPT reduced the biological effects of KIAA0247 knockdown, suggesting that KIAA0247 decreased the carcinogenic activity of NSCLC cells through downregulation of Notch signaling. Our results indicate that KIAA0247 inhibits NSCLC progression by reducing the metastatic potential of cancer cells through downregulation of the Notch pathway, which may underlie the association of KIAA0247 expression with favorable clinicopathological characteristics of NSCLC patients. These findings suggest that KIAA0247 is a candidate prognostic biomarker and potential therapeutic target in NSCLC.