Thrombotic thrombocytopenic purpura (TTP), a life-threatening syndrome characterized by acute microangiopathic hemolytic anemia, thrombocytopenia, and visceral ischemia, can be classified as congenital TTP (inherited due to a mutation in ADAMTS13) and acquired TTP. The acquired TTP is further classified as idiopathic and secondary TTP. Systemic lupus erythematosus (SLE) is regarded as one of the most common causes of secondary TTP (SLE-TTP). In contrast to patients with idiopathic TTP, some patients with SLE-TTP, especially those diagnosed with refractory TTP, are resistant to plasma exchange and high-dose corticosteroids and usually require second-line drugs, including newly developed biologicals. Belimumab, a B-lymphocyte stimulator-specific inhibitor, was the first approved new therapy for SLE in the past 50 years. Only two cases of SLE-TTP using belimumab have been reported; however, detailed information has not been made available. Herein, we describe a 28-year-old female patient who presented with palm petechiae, strong tawny urine, and yellow stained skin and sclera, and was diagnosed with SLE-TTP supported by high anti-ANA titers; positive anti-SSA/SM; pleural effusion; decreased platelet count, hemoglobin, and complement C3/C4 counts; increased lactate dehydrogenase level, along with increased schistocytes; and a significant deficiency of ADAMTS13 activity. Belimumab (10 mg/kg) was administered after six plasma exchanges. Good efficiency and outcomes without any adverse events, SLE, or TTP relapse were observed during 12 months of follow-up. Therefore, belimumab is a promising choice for SLE-TTP management. In addition, we provide a focused review of the existing literature on the pathogenesis, diagnosis, and therapeutic strategies for SLE-TTP.