Methotrexate is widely prescribed by various specialists, including internists, dermatologists, rheumatologists, orthopedics, and oncologists. The clinical features of acute methotrexate toxicity vary and are influenced by the acute cumulative dose, duration of methotrexate, associated risk factors, comorbidities, and drug interactions. We present a series of six patients with acute methotrexate toxicity. The characteristics of their clinical presentation, diagnoses, and risk factors are highlighted. All patients were given intravenous leucovorin and other supportive treatments. This series highlights the importance of thorough counseling for patients regarding the course of disease for which methotrexate is prescribed and the dosing, schedule, and adverse effects that are associated with methotrexate. Physician awareness, diagnosis, and treatment are crucial for mitigating the complications of methotrexate toxicity. (SKINmed. 2022;20:274-281).