Fusarium head blight (FHB) causes severe economic impacts by reducing yield and quality of small grain cereals, and poses health risks to both humans and animals via the accumulation of mycotoxins such as deoxynivalenol (DON). The use of endophytic fungi as potential biological control agents is an underexplored method for reducing the impact of FHB. There are several mechanisms through which endophytic fungi may affect biological control, including the production of antifungal secondary metabolites, resource competition with pathogens, and stimulation of innate plant defense responses. We determined that Sarocladium zeae, a known endophyte of corn that produces secondary metabolites inhibitory to Fusarium graminearum, is also able to colonize wheat extensively. Strains of S. zeae differ in their colonization ability, but S. zeae NRRL 34560 was shown to be a systemic endophyte of wheat, successfully colonizing the majority of internal plant organs and surviving within the plant through its life cycle. When allowed to pre-colonize wheat ahead of inoculation with F. graminearum, this strain significantly reduced FHB symptoms (57.9% reduction in area under the disease progress curve) and DON content in harvested wheat heads (61.2% reduction). While these protective effects may arise from multiple simultaneously acting mechanisms, we demonstrate that plant hormones related to defense signaling respond to the presence of S. zeae, indicating that defense priming may be an important mechanism leading to protection in this system.