We report a case of methotrexate (MTX)-induced stroke-like encephalopathy in an 18-year-old woman, with acute lymphoblastic leukemia, who developed a sudden neurological deficit mimicking a cerebrovascular event. Bain MRI showed hyperintensities on diffusion-weighted-imaging (DWI) with matching apparent diffusion coefficient hypointensities, which also represent the commonest MRI findings in acute cerebral infarction. DWI changes spared the cerebral cortex and did not respect vascular territories, supporting a non-vascular mechanism. MRI plays a crucial role in the diagnostic work-up and is essential to avoid unnecessary intervention such as thrombolytic therapy. Teaching Point: Methotrexate-induced stroke like neurotoxicity should be considered in patients treated with methotrexate and presenting with a stroke-like clinical picture and radiological findings consistent with acute cerebral infarction.