Over the course of a lifetime, humans may be exposed to different types of radiation, typically in the form of low-linear energy transfer (LET) radiation, which is used, for example, in cancer treatment. In addition, astronauts may be exposed to high-LET radiation in outer space. Here, we propose that alterations to the gastrointestinal (GI) microbiota may occur when exposure to either low- or high-LET radiation, and that these alterations may perturb important relationships that exist between the GI microbiota and human health. For example, the GI microbiota can communicate with the brain via various pathways and molecules, such as the enteric nervous system, the vagus nerve, microbial metabolites and the immune system. This relationship has been termed the “gut-brain axis”. Alterations to the composition of the GI microbiome can lead to alterations in its functional metabolic output and means of communication, therefore potentially causing downstream cognitive effects. Consequently, studying how radiation can affect this important network of communication could lead to new and critical interventions, as well as prevention strategies. Herein, we review the evidence supporting a relationship between radiation exposure and disruption of the gut-brain axis as well as summarize strategies that may be used to counter the effects of radiation exposure on the GI microbiome.