Abstract: Exercise-induced heat production is further elevated by exercise performed in hot conditions and this can subsequently impact inflammation, and gastrointestinal (GI) health. Implementing nutrition and supplementation strategies under these conditions may support the hyperthermic response, the systemic inflammatory response, GI permeability and integrity, and exercise performance. Therefore, the aim of this brief review is to explore athletes’ inflammatory response of two key biomarkers, lipopolysaccharide (LPS), and interleukin-6 (IL-6), and provide nutrition and supplementation recommendations when exercising in hot conditions. There is emerging evidence that probiotics, glutamine, and vitamin C can preserve GI integrity, which may improve performance during exercise in the heat. Glucose rich food when consumed with water, before and during exercise in the heat, also appear to limit endotoxemia, preserve GI integrity, and reduce the incidence of GI disturbances compared with water alone. The use of non-steroidal anti-inflammatory drugs (NSAIDs) may compromise GI integrity and this may result in greater leakage of endotoxins during long duration exercise in the heat. Further work is required to elucidate the impact of nutrition and supplementation strategies, in particular the use of NSAIDs, when exercising in the heat