As one of the most common abiotic stresses, salt stress seriously impairs crop yield. Brachypodium distachyon (L.) Beauv. is a model species for studying wheat and other grasses. In the present investigation, the physiological responses of B. distachyon treated with different concentrations of NaCl for 24 h were measured. Therefore, the control and the seedlings of B. distachyon treated with 200 mM NaCl for 24 h were selected for transcriptome analysis. Transcriptome differential analysis showed that a total of 4116 differentially expressed genes (DEGs) were recognized, including 3120 upregulated and 996 downregulated ones. GO enrichment assay indicated that some subsets of genes related to the active oxygen scavenging system, osmoregulatory substance metabolism, and abscisic-acid (ABA)-induced stomatal closure were significantly upregulated under salt stress. The MapMan analysis revealed that the upregulated genes were dramatically enriched in wax metabolic pathways. The expressions of transcription factor (TF) family members such as MYB, bHLH, and AP2/ERF were increased under salt stress, regulating the response of plants to salt stress. Collectively, these findings provided valuable insights into the mechanisms underlying the responses of grass crops to salt stress.