Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that has been proposed as a safe and effective nonopioid analgesic when given in lower doses than those historically used for general anesthesia. Case reports have demonstrated efficacy using low-dose ketamine for pain management and opioid weaning in patients with chronic noncancer pain, but reports of successful use in patients with sickle cell pain are limited. A 35-year-old African American male with sickle cell disease presented to the emergency department with severe generalized body aches and left flank pain. Several days later, his pain became localized to the bilateral lower extremities. Escalating opioid doses provided no improvement. Workup was negative for infection, deep venous thrombosis, ischemia, and infarct. On hospital day 29, the Acute Pain Management Service was consulted and initiated a low-dose ketamine infusion for analgesia and to facilitate opioid weaning. Five days later, the patient was discharged pain-free. Ketamine is a potent nonopioid analgesic, and this report adds to the body of literature supporting the use of low-dose ketamine in patients with sickle cell disease to treat poorly controlled pain and opioid-induced hyperalgesia.