Acute ischemia of the bowel is a rare but life-threatening diagnosis in the emergency department (ED). While early detection is key to appropriate management, the utility of investigative modalities is limited by poor sensitivity and specificity. This report outlines the case of a 37-year-old female patient who presented to a tertiary hospital ED with severe, generalized, abdominal pain for several hours after eating at a restaurant. She had a known history of treatment for breast cancer, on chemotherapy, and was also diagnosed with dihydropyrimidine dehydrogenase (DPD) deficiency. Laboratory investigations, including C-reactive protein and full blood counts (FBCs), were not significantly suggestive of bowel ischemia, and CT abdomen and pelvis with intravenous (IV) contrast and angiogram revealed no obvious vascular occlusion. Severe, persistent pain out of proportion to physical examination raised suspicion of a non-occlusive mesenteric ischemia (NOMI), and a diagnostic laparotomy was performed, uncovering an infarcted duodenal segment that underwent resection and anastomosis. Post-op, the patient recovered well and was discharged without complications. Given the absence of typical risk factors, such as advanced age, atrial fibrillation, coagulopathy, cardiac disease, or a low-flow state in our patient, we explore the association of chemotherapeutic agents with NOMI, as well as the implications of DPD deficiency. A high index of suspicion for mesenteric ischemia should be maintained for any patient with severe, intractable abdominal pain, out of proportion to the clinical examination, even in the absence of conventional risk factors. Patients with malignancies may require additional consideration of ischemia risk from the use of chemotherapeutic agents, with possibly an increased risk with platinum-based compounds. Known DPD deficiency may also worsen chemotherapeutic drug-related toxicities, although its implication in ischemia is not well established.