Methotrexate (MTX), an anti-metabolite, is part of various chemotherapy regimens to treat acute lymphoblastic leukemia (ALL) and certain non-Hodgkin's lymphomas (NHLs). It is the major drug used in central nervous system (CNS) prophylaxis. Besides, its common hepatic, pulmonary, and hematologic toxicities, it has been implicated in the development of toxic leukoencephalopathy. Here, we present a case of a 19-year female, diagnosed with T-ALL. She was managed with UK ALL 2011 regimen B induction as a standard of care and intrathecal MTX as CNS prophylaxis. She tolerated induction well; however, during the second block of consolidation, she started developing lower limb weakness, inability to stand, unilateral weakness and aphasia. Her condition worsened rapidly over the next 24 hours leading to paraplegia and ultimately quadriplegia. Within 48 hours from onset of symptoms, she had lost all her motor functions, potentially leading to impending apnoea. We placed her on mechanical ventilation. MRI brain showed drug (MTX)-induced leukoencephalopathy (LE). In most cases, recovery starts within 5-7 days and by the 3rd week, majority have usually recovered. However, cases of irreversible neurologic damage and late-onset chronic toxicities have been reported. Key Words: Methotrexate, Leukoencephalopathy, Chemotherapy, Leukemias.