A 43-year-old Saudi man with prediabetes presented with epigastric pain and thrombocytopenia, initially treated as immune thrombocytopenia with dexamethasone. The patient’s condition worsened as he developed a rash and hematuria, prompting hospital transfer and a severe drop in platelet count. Despite platelet transfusions and steroids, he showed no improvement, leading to a suspected diagnosis of thrombotic thrombocytopenic purpura (TTP). The patient’s anti-nuclear antibody (ANA) test result was positive. This may be because individuals are more likely to develop an autoimmune disease for up to 12 years following an acute TTP episode. After initial plasmapheresis sessions, he was admitted to the ICU for further management. Diagnostic workup, including ADAMTS13 assay, confirmed primary immune-mediated thrombotic thrombocytopenic purpura (iTTP), leading to the initiation of plasmapheresis and rituximab. After he responded to therapy, plasma exchange (PEX) was discontinued, and his platelet count began to decline. On the third day after discontinuation, his platelet count decreased to 80,000 x 10⁹/L, necessitating the restart of PEX. During treatment, the patient experienced transient neurological symptoms and developed a pulmonary embolism, which was managed with anticoagulation. Plasmapheresis and immunosuppressive therapy resulted in clinical improvement in stabilizing platelet counts, and he was discharged in good condition after 16 sessions of plasmapheresis and three doses of rituximab. This case highlights the diagnostic challenges in atypical TTP presentations and underscores the importance of promptly identifying TTP and initiating aggressive therapy.