Sickle Cell Disease (SSD) can present with acute painful crises, most commonly manifesting as diffuse bony pain; however, rare presentations of acute coronary syndrome, acute papillary necrosis, or multi-organ failure may also present in these patients. TTP has been rarely described in conjunction with sickle cell pain crisis (SS crisis). In both TTP and sickle cell crises, widespread platelet activation is present with thrombocytopenia as a result. Thrombocytopenia can be utilized as a poor prognostic indicator in patients with SS crisis. Multi-organ failure may appear similar to TTP and patients may benefit from similar therapy. Here, we present a 27-year-old female with a history of SSD who presented with a painful crisis who was found to have worsening renal failure and thrombocytopenia and was treated empirically with therapeutic plasma exchange (TPE), later discovered to have SS crisis with multi-organ failure with unremarkable ADAMSTS13 values. Given the high fatality risk of TTP, the benefits outweighed the risks for empiric TPE therapy, and our patient benefited from the treatment, as patients with both TTP and/or SS crisis multi-organ failure have demonstrated improvement following this treatment. Given the severity of multi-organ failure in SSD patients, additional research is warranted for improvement in the diagnosis and management of these patients.