Methotrexate is an anti-metabolite, anti-cancer drug frequently used in the treatment of extensive chronic plaque psoriasis. Psoriatic plaque erosion is a rare toxic side effect of single-dose methotrexate and is described as a sign of impending pancytopenia. Here, we report a case of a 48- year-old male presented with multiple oral and genital erosions, accompanied by fissuring over palm and soles for 5 days. His laboratory tests revealed severe pancytopenia and nephropathy. He had a history of chronic plaque psoriasis for which he took a single dose of 15 mg methotrexate. During the hospital stay, the patient needed folate antagonist, granulocyte colony-stimulating factor (G-CSF), intravenous fluids, blood transfusions, and platelet transfusions. He recovered within 12 days of admission.