Gastrointestinal amyloidosis (GIA), a protein deposition disorder, represents a complex common pathway that encompasses multiple etiologies and presentations. It represents a significant diagnostic and treatment challenge. The disease results from the deposition of insoluble extracellular protein fragments that have been rendered resistant to digestion. GIA can be acquired or genetic, and most commonly results from chronic inflammatory disorders (AA amyloidosis), hematologic malignancy (AL amyloidosis), and end-stage renal disease (Beta-2 amyloidosis). The deposition of these abnormal proteins interferes with gastrointestinal tract (GI) organ structure and function, most notably in the liver and small bowel. Presentation from GI involvement includes cirrhotic sequelae, abdominal pain, malabsorption, and GI bleeding. Diagnosis hinges on pathologic examination of affected tissue, with classic green birefringence under polarized light. Abdominal fat pad and rectal mucosal biopsy have been described as sites of higher sensitivity for diagnosis. Serum amyloid P scintigraphy is near 90% sensitive for diagnosis of AA amyloidosis. Patients should be considered for further evaluation to rule out additional organ involvement, notably cardiac and renal. Treatment hinges on an adequate suppression of the predisposing inflammatory disorder, or malignancy, followed by supportive therapy. Prognosis varies depending on the etiology of the disease, with the AL subtype showing worse outcomes, as well as those with hepatic involvement.