Drug resistance is one of the leading causes of chemotherapy failure in cancer treatment. MicroRNAs (miRNAs or miRs) are short non-coding RNA molecules that post-transcriptionally regulate gene expression and play a critical role in diverse biological processes. In this study, we report that miR-503 regulates the resistance of non-small cell lung cancer cells to cisplatin. The expression of miR-503 was decreased in the cisplatin-resistant non-small cell lung cancer cells, A549/CDDP, compared with the parental A549 cells. The overexpression of miR-503 sensitized the A549/CDDP cells to cisplatin, whereas the inhibition of miR-503 in the A549 cells increased resistance to cisplatin. Mechanistically, miR-503 specifically targeted Bcl-2, an anti-apoptotic protein upregulated in the A549/CDDP cells. The ectopic expression of miR-503 reduced the Bcl-2 protein level and sensitized the A549/CDDP cells to cisplatin-induced apoptosis. Taken together, our results suggest that miR-503 regulates cell apoptosis, at least in part by targeting Bcl-2, and thus modulates the resistance of non-small cell lung cancer cells to cisplatin.