Silicon plays a vital role in plant growth. However, molecular mechanisms in response to silicon have not previously been studied in wheat. In this study, we used RNA-seq technology to identify differentially expressed genes (DEGs) in wheat seedlings treated with silicon. Results showed that many wheat genes responded to silicon treatment, including 3057 DEGs, of which 6.25% (191/3057) were predicted transcription factors (TFs). Approximately 14.67% (28 out of 191) of the differentially expressed TFs belonged to the MYB TF family. Gene ontology (GO) enrichment showed that the highly enriched DEGs were responsible for secondary biosynthetic processes. According to KEGG pathway analysis, the DEGs were related to chaperones and folding catalysts, phenylpropanoid biosynthesis, and protein processing in the endoplasmic reticulum. Moreover, 411 R2R3-MYB TFs were identified in the wheat genome, all of which were classified into 15 groups and accordingly named S1-S15. Among them, 28 were down-regulated under silicon treatment. This study revealed the essential role of MYB TFs in the silicon response mechanism of plants, and provides important genetic resources for breeding silicon-tolerant wheat.