MicroRNA-630 (miR-630) plays dual roles in tumor progression in various human cancers. However, the role of miR-630 in chemoresistance and prognosis in non-small cell lung cancer (NSCLC) remains to be elucidated. This retrospective study enrolled 114 surgically resected patients with NSCLC who experienced tumor relapse and underwent cisplatin-based chemotherapy. The aim was to examine the possible association between miR-630 (and its targeting of Bcl-2 expression) and the response to cisplatin-based chemotherapy. Patients with tumors expressing low miR-630, high Bcl-2, and a combination of both were more likely than their counterparts to show unfavorable responses to cisplatin-based chemotherapy. Kaplan-Meier and Cox regression analysis indicated that low miR-630, high Bcl-2, and a combination of both may independently predict poor overall survival and short relapse-free survival in patients with NSCLC. Six types of NSCLC cells were collected to determine the inhibitory concentration of cisplatin yielding 50% viability (IC50) by the MTT assay. The IC50 value for cisplatin was negatively correlated with miR-630 expression levels among these cell types, except for A549 cells. Mechanistically, low miR-630 expression conferred cisplatin resistance and colony formation by de-targeting Bcl-2 in NSCLC cells. We therefore suggest that low miR-630, high Bcl-2, and a combination of both may potentially predict an unfavorable chemotherapeutic response and poor outcome in patients with NSCLC.