Duodenal adenocarcinoma (DA) is a rare tumor. We present the case of an 84-year-old lady who presented with episodic emesis with progressive dysphagia to solids and liquids. She also noted a significant weight loss of 31kg over four months. She was reported to have multiple brain masses three months before this admission. A computed tomography (CT) scan showed a heterogeneous mass (8cm) in the left retroperitoneum, inseparable from the duodenum. Additional peritoneal nodules and enlarged retroperitoneal lymph nodes were suspicious for metastases. Esophagogastroduodenoscopy revealed extrinsic compression of the stomach by the tumor. A large friable distal duodenal mass (fourth part) partially obstructed the lumen, which was biopsied. Pathology results demonstrated high-grade dysplasia but did not confirm malignancy. The patient's carcinoembryonic antigen (CEA) was elevated, but cancer antigens (CA)125 and CA19-9 were normal. A percutaneous biopsy of the mass revealed enteric-type adenocarcinoma. Immunohistochemistry showed that the tumor was positive for caudal-type homeobox (CDX)2, negative for special AT-rich sequence-binding protein (SATB)2, and patchy positive for cytokeratin (CK)7 and CK20 staining. The collective evidence suggested a duodenal primary. The patient opted for hospice and died in three days. We lack pathological evidence, but the patient's brain masses were suspicious of metastases. This would be one of the few reported cases of DA with possible brain metastases.