Septoria tritici blotch (STB) is an important foliar disease of wheat that is caused by the fungal pathogen Zymoseptoria tritici. The grass Brachypodium distachyon has been used previously as a model system for cereal-pathogen interactions. In this study, we examined the nonhost resistance (NHR) response of B. distachyon to two different Z. tritici isolates in comparison with wheat. These isolates vary in aggressiveness on wheat cultivar Remus, displaying significant differences in disease and pycnidia coverage. Using microscopy, we found that similar isolate-specific responses were observed for hydrogen peroxide accumulation and cell death in both wheat and B. distachyon. Despite this, induction of isolate-specific patterns of defense gene expression by Z. tritici did differ between B. distachyon and wheat. Our results suggest that expression of the phenylalanine ammonia lyase PAL gene may be important for NHR in B. distachyon, while pathogenesis-related PR genes and expression of genes regulating reactive oxygen species may be important to limit disease in wheat. Future studies of the B. distachyon-Z. tritici interaction may allow identification of conserved plant immunity targets that are responsible for the isolate-specific responses observed in both plant species.