Background: MiRNAs have been recently implicated in the pathogenesis underlying ischemia-reperfusion (IR) injury. We investigated the miRNAs expression profiles in the early stages after lung transplantation (LT) and studied the involvement of Toll-like receptor(TLR) signaling pathway in lung IR injury following LT. Methods: We established the left LT model in mice, The mice were injected with a miRNA-122 specific inhibitor, following which pathological changes in the lung tissue were studied using different lung injury indicators. In addition, we performed deep sequencing in transplanted lung tissues to indentify differentially expressed (DE) miRNAs and their target genes. Results: A total of 12DE miRNAs were selected and 2,476 target genes were identified; The gene ontology (GO) enrichment analysis predicted 6,063 terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis predicted 1,554 biological pathways. Compared with the control group, inhibiting the expression of miRNA-122 significantly reduced the lung injury and lung W / D ratio (p<0.05). In addition, the activity of myeloperoxidase (MPO) and expression of tumor necrosis factor (TNF)-α and TLR2/4 decreased (p<0.05); whereas the expression of interleukin-10(IL-10) expression levels increased (p<0,05). Furthermore, the inhibition of miRNA-122 suppressed the IR injury-induced activation of the TLR signaling pathway. Conclusions: Our findings showed the differential expression of several miRNAs in the early inflammatory response following LT. Of these, miRNA-122 promoted the IR injury following LT, whereas its inhibition prevented IR injury in a TLR-dependent manner.