Superior mesenteric artery syndrome (SMAS) is an uncommon condition, attributable to vascular compression of the third part of the duodenum between the superior mesenteric artery and the abdominal aorta. It can present in patients due to mechanical compression or severe weight loss. We present a unique case of SMAS in a patient undergoing carboplatin-based chemotherapy for mesothelioma. An 81-year-old male with mesothelioma was treated with carboplatin-based chemotherapy. He subsequently suffered a progressive, unintentional 18 kg weight loss and presented acutely with intense epigastric pain, severe nausea, and vomiting. Diagnosis was confirmed by abdominal computed tomography and esophagogram with upper gastrointestinal series, which revealed gastric and duodenal distention and a narrow angle between the superior mesenteric artery and aorta, causing compression of the duodenum. Prompt recognition of this syndrome allowed us to treat our patient successfully and avoid the risks of operative interventions. To our knowledge, this is the first reported case of SMAS in patients receiving carboplatin. Furthermore, this case of SMAS was unique in that it was due to weight loss as compared with mechanical obstruction. Our experience illustrates the importance of considering SMAS in chemotherapy patients, especially those with substantial weight loss. A high index of suspicion for this potential complication coupled with appropriate radiographic studies are necessary for early diagnosis and can prevent severe consequences.