This study aimed to explore key regulatory connections underlying lung transplant rejection. The differentially expressed genes (DEGs) between rejection and stable lung transplantation (LTx) samples were screened using R package limma, followed by functional enrichment analysis and protein-protein interaction network construction. Subsequently, a global triple network, including miRNAs, mRNAs, and transcription factors (TFs), was constructed. Furthermore, immune cell infiltration characteristics were analyzed to investigate the molecular immunology of lung transplant rejection. Finally, potential drug-target interactions were generated. In brief, 739 DEGs were found between rejection and stable LTx samples. PTPRC, IL-6, ITGAM, CD86, TLR8, TYROBP, CXCL10, ITGB2, and CCR5 were defined as hub genes. Eight TFs, including STAT1, SPIB, NFKB1, SPI1, STAT5A, RUNX1, VENTX, and BATF, and five miRNAs, including miR-335-5p, miR-26b-5p, miR-124-3p, miR-1-3p, and miR-155-5p, were involved in regulating hub genes. The immune cell infiltration analysis revealed higher proportions of activated memory CD4 T cells, follicular helper T cells, γδ T cells, monocytes, M1 and M2 macrophages, and eosinophils in rejection samples, besides lower proportions of resting memory CD4 T cells, regulatory T cells, activated NK cells, M0 macrophages, and resting mast cells. This study provided a comprehensive perspective of the molecular co-regulatory network underlying lung transplant rejection.