Management of terminal ileal Crohn disease (CD) is difficult due to fibrotic prognosis and failure to achieve mucosal healing. A limited number of synchronous analyses have been conducted on the transcriptome and microbiome in unpaired terminal ileum tissues. Therefore, our study focused on the transcriptome and mucosal microbiome in terminal ileal tissues of patients with CD with the aim of determining the role of cross-talk between the microbiome and transcriptome in the pathogenesis of terminal ileal CD. Mucosa-attached microbial communities were significantly associated with segmental inflammation status. Interaction-related transcription factors (TFs) are the panel nodes for cross-talk between the gene patterns and microbiome for terminal ileal CD. The transcriptome and microbiome in terminal ileal CD can be differently related to the local inflammatory status, and specific differentially expressed genes may be targeted for mucosal healing. TFs connect gene patterns with the microbiome by reflecting environmental stimuli and signals from microbiota.