Aim: To study a rare presentation of acute leukoencephalopathy with acute chest syndrome and pulmonary infarction all at once in a patient of sickle cell disease (SCD). Background: Acute leukoencephalopathy with acute chest syndrome is a very rare complication in a patient with SCD. Both complications occur due to vaso-occlusive crisis. Acute chest syndrome presents with fever, cough, shortness of breath, and pulmonary thromboembolism as a likely etiology. Acute leukoencephalopathy usually presents as posterior reversible leukoencephalopathy (PRES) characterized by headache, seizure, encephalopathy, visual symptoms, and focal neurological deficits. Magnetic resonance imaging (MRI) findings usually reveal edematous changes in the occipital and parietal lobes. Case description: Hereby, we present a case of acute leukoencephalopathy with acute chest syndrome with pulmonary infarct (due to pulmonary thromboembolism) in a case of SCD with the help of clinical, laboratory, and radiological correlation. In this case, an MRI brain showed involvement of the frontal lobe, thalamus, and cerebellum, which is an extremely rare presentation. The patient was given antibiotics, bilevel-positive airway pressure (BiPAP) support, and steroids, as a result of which the patient showed significant clinical improvement. Conclusion and clinical significance: In this case, we concluded that leukoencephalopathy can involve atypical areas with acute chest syndrome, which is very rare in the adult population and is a matter of clinical significance for future research.