Thrombotic thrombocytopenic purpura (TTP) is an uncommon life-threatening condition characterized by hemolytic disorders. The coexistence of systemic lupus erythematosus (SLE) with TTP is extremely rare, although Africans are at increased risk due to inherited risk factors. This report describes a rare clinical manifestation of TTP associated with SLE in a Sudanese patient. A 41-year-old Sudanese woman presented to the emergency department with symptoms and features that were suggestive of malaria, for which she had been treated accordingly. However, a few days later she complained of fever, and was found to have a body temperature of 39.5°C, jaundice, anemia, and thrombocytopenia. Soon after admission, she developed confusion and unrecordable blood pressure. After the patient had stabilized, clinical assessment, immune-system investigation (antinuclear antibody profile, complements, blood panel), and imaging revealed a diagnosis of TTP associated with SLE. The patient received imipenem 500 mg, five sessions of plasmapheresis (60 mL/kg), methylprednisolone 1 g pulse for 3 days, and rituximab 375 mg/week. Three weeks later, the patient was discharged after her condition had improved, and she is now on regular follow-up.