Methylmalonic academia (MMA) is a rare inborn error of branched-chain amino acid metabolism. Therapy consists of a special formulated protein diet, carnitine supplementation, and emergent detoxification during acute decompensation. Continuous hemodiafiltration is a modality choice to treat acute metabolic decompensation in inborn error of metabolism. We report the successful use of continuous hemodiafiltration in the management of acute decompensation in patients with methylmalonic academia. Three male patients were diagnosed with methylmalonic academia with the initial presentation of hyperammonemia. Continuous hemodiafiltration was utilized to treat acute decompensation of metabolic crisis. This approach results in a rapid reduction of systemic toxin levels. Continuous hemodiafiltration should be considered as a treatment modality for symptomatic neonates with MMA where hemodialysis is not feasible.