Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal disorder that requires urgent identification and treatment. The association of TTP with systemic lupus erythematosus (SLE) and vasculitis has been reported, however, never simultaneously. A 33-year-old woman with a history of SLE presented with acute abdominal pain, fever, arthralgias, and skin rash. She had acute severe hypertension, diffuse abdominal tenderness, and petechial rash. Diagnostic work-up revealed active urine sediment with proteinuria and hematuria and elevated creatinine, anemia, and thrombocytopenia. She was diagnosed with acute lupus nephritis and early microangiopathic hemolytic anemia in the setting of hypertensive urgency and started on intravenous methylprednisolone 500 mg once a day. Within 48 hours, she developed shock with multiorgan dysfunction and succumbed to her illness. Laboratory tests later showed ADAMTS13 activity less than 10% consistent with TTP and p-antineutrophil cytoplasmic antibody (ANCA) positivity. Autopsy revealed small-vessel vasculitis of the visceral organs. Kidney biopsy demonstrated diffuse proliferative glomerulonephritis. This case illustrates the occurrence of SLE nephritis, p-ANCA vasculitis, and severe TTP with rapidly fatal course, and the importance of having a low threshold for initiating plasma exchange therapy. Here, we discuss the case and provide a literature review on cases of TTP with SLE and vasculitis.