In patients with lung cancer, myeloid-derived suppressor cells (MDSCs) have been reported to be significantly increased. Tumor-derived exosomes (TDEs) from various cancers played a critical role in MDSC induction. However, studies on the molecular mechanism underlying MDSC expansion induced by exosomes from lung cancer cells are still limited. In this study, we demonstrated that LLC-Exo accelerated tumor growth along with a significant accumulation of MDSCs in mouse tumor model. miRNA profiling showed that miR-21a was enriched in LLC-Exo. The depletion of miR-21a in LLC-Exo leads to the loss of their ability to induce MDSC expansion. Further results showed that miR-21a of LLC-Exo induced MDSC expansion via downregulation of the programmed cell death protein 4 (PDCD4) protein. The results of gain-and loss-of-function experiments validated that PDCD4 function as a critical inhibitor to negatively regulate expansion of MDSCs via inhibition Il-6 production in bone marrow cells. In addition, our data showed that exosomes derived from human lung cancer cell lines expressing miR-21a, also induced expansion of MDSCs in human CD14+ monocytes in vitro. Overall, our results demonstrated that miR-21a enriched in lung carcinoma cell-derived exosomes could promote functional expansion of MDSCs through targeting PDCD4.