Self-reported food intolerances are estimated to affect between 15–20% of the population. Among them, histamine intolerance (HIT) has emerged as a focus of particular interest. It is defined as a disequilibrium between dietary histamine and the capacity of the organism to degrade intestinal histamine, leading to the appearance of intestinal and extra-intestinal symptoms. HIT is thought to be associated with low activity or blockade of diamine oxidase (DAO), the main enzyme for histamine degradation. The diagnosis is hampered by the lack of a validated biomarker and is mainly based on clinical assessment and response to a low histamine diet and reintroduction. The therapeutic approach is centered on dietary management, restricting foods that may increase circulating histamine levels. DAO supplementation has been shown to potentially contribute to histamine degradation in the intestinal lumen, but its activity varies depending on the presence of cofactors and the enzyme’s origin. Limited clinical evidence reflects the difficulty of dietary management and suggests a beneficial role of DAO supplementation on the clinical manifestations associated with HIT.