Systemic autoinflammatory syndromes (SAIS) are a heterogeneous group of rare hereditary diseases characterized by seemingly unprovoked antigen-independent pathologic inflammation. These disorders result from a genetic defect in the innate arm of the immune response. Unlike autoimmune diseases, which result from defects in the adaptive component of the immune system, autoinflammatory syndromes usually lack the tissue-specific autoantibodies and the autoreactive T lymphocytes but possess other local tissue factors that induce the inflammatory response; this is a central differentiating point between autoinflammatory and autoimmune diseases. Gut involvement in systemic autoinflammation has been reported in the earliest descriptions. It may be either primary being a cardinal feature of the disease, a secondary feature related to medications, or just an association. Paediatric Bechet's disease, Very Early Onset Inflammatory bowel disease (VEOIBD), Haploinsufficiency of A20, Familial Mediterranean fever (FMF), NLRC4, Mevalonate kinase deficiency, and DAD2 deficiency are examples of SAIS with GIT manifestations. Thorough clinical evaluation with consideration of the possible differential diagnoses remains the cornerstone in the initial assessment of a patient, to provide the framework for subsequent investigations and management. Genetic testing is increasingly used in the diagnosis and guiding therapeutic process. Emerging targeted treatments can be curative, control flares, and minimize sequelae.