Background Cd accumulation in plant cells results in dramatic problems including oxidative stress and inhibition of vital enzymes. It also affects mineral uptakes by disrupting membrane permeability. Interaction among Cd and other plant nutrient elements changes the nutritional contents of crops and reduces their yield. Methods and results In the present study, Cd stress in Brachypodium distachyon led to the upregulation of some heavy metal transport genes (influx or efflux) encoding cation-efflux proteins, heavy metal-associated proteins and NRAMP proteins. The Arabidopsis orthologs of the differentially expressed B. distachyon genes (DEGs) under Cd toxicity were identified, which exhibited Bradi4g26905 was an ortholog of AtALY1-2. Detailed co-expression network and gene ontology analyses found the potential involvement of the mRNA surveillance pathway in Cd tolerance in B. distachyon. These genes were shown to be downregulated by sulfur (S) deficiency. Conclusions This is the first transcriptomic study investigating the effect of Cd toxicity in B. distachyon, a model plant for genomic studies in Poaceae (Gramineae) species. The results are expected to provide valuable information for more comprehensive research related to heavy metal toxicity in plants.