Background Methotrexate (MTX) toxicity can manifest following high-dose methotrexate infusion (HDMTX), leading to acute kidney injury (AKI), hepatitis, mucositis, and myelosuppression. The management and prevention of toxicity-related conditions include urine alkalinization, leucovorin administration, and glucarpidase treatment. In some cases, extracorporeal removal techniques are necessary. This case series reports on pediatric patients who experienced acute MTX toxicity and were effectively treated with low-flux Hemodialysis (HD). Methods This study included patients who required hemodialysis due to AKI and elevated MTX levels following MTX infusion between 2012 and 2021. Data on MTX levels before and after HD sessions, laboratory findings, complications, and length of hospital stay were recorded for each patient. Results Six pediatric patients were admitted to our center due to increased serum MTX levels following HDMTX treatment. All were treated with low-flux HD. At 36 hours post-MTX administration at a median dose of 7 gr/m^2, plasma MTX levels ranged from 14 to 225 µmol/L (median 20.46 µmol/L), and baseline creatinine levels increased to a median of 2.75 times the baseline. HD was initiated at a median of 55 hours post-MTX infusion. Approximately 70% (ranging from 59.2% to 82%) of methotrexate was removed in the initial HD session using a polysulfone low-flux dialyzer. A total of 19 HD sessions were conducted without any HD-related complications. Conclusion The current study demonstrates that patients can experience AKI and MTX toxicity following HDMTX treatment and that conventional HD, comparable to high-flux dialyzers, is effective in improving AKI conditions and mitigating severe toxic side effects by accelerating the elimination process. While glucarpidase is considered the most effective agent for MTX elimination according to the latest systematic review (EXTRIP Workgroup), we propose that conventional HD remains a viable option in resource-limited settings.