Fat embolism syndrome is a relatively infrequent presentation in sickle cell thalassemia patients. It most commonly occurs in long bone fractures in the setting of trauma. However, nonorthopedic trauma and nontraumatic cases have been reported to contribute to fat embolism. The fat embolic syndrome is an underdiagnosed, life-threatening, and debilitating complication of sickle-β-thalassemia-related hemoglobinopathies. It is primarily seen in milder versions of sickle cell disease, including HbSC and sickle cell β-thalassemia, with the mild prior clinical course without complications; hence, diagnosis can be easily missed. Pathogenesis of fat embolic syndrome is a combination of mechanical obstruction from fat globules released into systemic circulation at the time of bone marrow necrosis and direct tissue toxicity from fatty acids and inflammatory cytokines released from fat globules. Prompt diagnosis and early initiation of treatment can reduce morbidity and mortality and result in better outcomes and prognosis. Red cell exchange transfusion is the mainstay of therapy with mortality benefits. Overall mortality and neurological sequelae continue to be high despite increased red cell exchange transfusion in the last few years. In this article, we discussed a case of a 34-year-old male patient with a history of sickle cell thalassemia and avascular necrosis of the hip, who presented with fever, hypoxia, encephalopathy, and generalized body aches, found to have thrombocytopenia and punctate lesions on magnetic resonance imaging brain, which led to the diagnosis of the fat embolism syndrome. Only a few sickle cell β-thalassemia with fat embolic syndrome cases have been reported.