Amyloidosis is the process of extracellular deposition of protein fibrils and manifests pathologically as a systemic or localized process. Localized amyloidosis of the head and neck is uncommon, and involvement of the sphenoid sinus is exceedingly rare. We describe a case of localized amyloidosis isolated from the sphenoid sinus. A descriptive literature search was conducted to highlight presentation, management, and outcomes related to this pathology. Our patient was a 65-year-old male who presented to our clinic with nasal congestion and an incidental finding of a large expansile mass within the sphenoid sinuses. The mass was seen to displace the pituitary gland, and thus a multidisciplinary care approach ensued. The mass was removed via a transnasal endoscopic approach. Pathology revealed fibrocollagenous tissue with calcifications that were positive on Congo red staining. The patient underwent further workup to rule out systemic involvement, which was unremarkable. Based on the findings of his workup, he was ultimately diagnosed with localized amyloidosis. A comprehensive review of the literature revealed 25 other reported cases of localized amyloidosis within the sinonasal region, with only one other case of isolated sphenoid sinus disease. Common presenting symptoms are nonspecific and may mimic other, more frequently seen regional pathologies, including nasal obstruction, rhinorrhea, and epistaxis. The treatment for localized disease is surgical resection. While localized amyloidosis within the sinonasal region is rare, it is important to recognize, work up, and treat it appropriately. A multidisciplinary team approach is necessary for appropriate diagnosis and management, and these patients should be followed closely after treatment.