Abstract Background The production of cereal crops is frequently affected by diseases caused by Fusarium graminearum and Magnaporthe oryzae, two devastating fungal pathogens. To improve crop resistance, many studies have focused on understanding the mechanisms of host defense against these two fungi individually. However, our knowledge of the common and different host defenses against these pathogens is very limited. Results In this study, we employed Brachypodium distachyon as a model for cereal crops and performed comparative transcriptomics to study the dynamics of host gene expression at different infection stages. We found that infection with either F. graminearum or M. oryzae triggered massive transcriptomic reprogramming in the diseased tissues. Numerous defense-related genes were induced with dynamic changes during the time course of infection, including genes that function in pattern detection, MAPK cascade, phytohormone signaling, transcription, protein degradation, and secondary metabolism. In particular, the expression of jasmonic acid signaling genes and proteasome component genes were likely specifically inhibited or manipulated upon infection by F. graminearum. Conclusions Our analysis showed that, although the affected host pathways are similar, their expression programs and regulations are distinct during infection by F. graminearum and M. oryzae. The results provide valuable insight into the interactions between B. distachyon and two important cereal pathogens.