Dysbiosis, which is an imbalance of gut microbial composition and function, can be caused by several external as well as internal factors, contributing to the onset of human and animal disorders, not limited to the gastrointestinal tract. Accordingly, the mechanisms leading to disease development involve a crucial interaction between the gut microbiota, their metabolic products, and the host. The expanded endocannabinoid system, also known as the “endocannabinoidome”, includes endocannabinoids (e.g., anandamide) and endocannabinoid-like mediators (e.g., palmitoylethanolamide), their receptors and metabolic enzymes. Dysregulation of this newly recognized endogenous system is also involved in several diseases. It is becoming increasingly apparent that a link between the endocannabinoidome and the gut microbiome exists. Here, we review some of the latest discoveries related to the functional link between these two complex systems and the disorders emerging from the malfunctioning of such a mutual interaction: for example, idiopathic inflammation, chronic enteropathies, metabolic disease and certain neuroinflammatory disorders. It is expected that in the near future new nutritional tools will emerge based on the expanding knowledge in this cutting-edge field.