High-dose methotrexate (HD-MTX) with rigorous supportive care is essential to the treatment of pediatric non-Hodgkin lymphomas (NHL). We describe the safety and tolerability of HD-MTX in patients with NHL treated at our center. In our cohort of 46 patients, the majority had at least one course of delayed clearance and/or creatinine elevation. Additionally, more than one-third of patients experienced an episode of grade ≥3 mucositis. Creatinine elevations and delayed clearance were independently associated with subsequent grade ≥3 mucositis. We advocate for greater availability of methotrexate monitoring to allow dose escalation of this essential modality around the world.