Cancer cells that develop resistance to cisplatin (DDP) are a major clinical obstacle to the successful treatment of cancer, including non-small cell lung cancer (NSCLC). Recent studies have implicated dysregulation of microRNAs (miRNAs) function in chemoresistance. Here, we explored the role of let-7c in the acquisition of DDP-resistant phenotype in A549 cells. Let-7c was downregulated in A549/DDP cell compared with A549 cells. Modulation of let-7c altered the sensitivity of A549/DDP cells to DDP through regulating DDP-induced apopotis. Furthermore, ABCC2 and Bcl-XL were identified as targets of let-7c. ABCC2 and Bcl-XL knockdown increased DDP sensitivity and DDP-induced apoptosis in A549/DDP cells. In conclusion, our findings suggested for the first time that let-7c modulate DDP response in A549/DDP cells, and one of the mechanisms was through targeting ABCC2 and Bcl-XL. Thus, let-7c could be considered for potential therapeutic application for modulating DDP-based therapy.