The restrictive element-1 silencing transcription factor (REST) is a transcriptional repressor which acts via epigenetic remodeling to silence numerous target genes. Emerging evidence indicates that REST is a master regulator of neuron-specific genes, not only in neurogenesis and neuronal differentiation, but also in differentiated neurons during postnatal brain development, where it plays a role in fine-tuning of genes involved in synaptic plasticity, and in normal aging, where it promotes neuroprotection by repressing genes involved in oxidative stress and dementia. However, un aberrant REST accumulation is involved in the pathophysiology of several neurological disorders, such as Huntington’s disease, epilepsy and stroke. In this study we investigated whether REST could have a determinant role in Amyotrophic Lateral Sclerosis pathophysiology. Here we found that REST protein significantly increased in motor cortex, brainstem and spinal cord of SOD1-G93A mice compared to WT mice, either during early-symptomatic phase or late stage of the disease. Notably, intracerebroventricular injection of a small interference RNA against REST (siREST) improved behavioral performance, reduced astrogliosis, reduced the formation of SOD1 aggregates and increased survival of SOD1-G93 mice. Our data show for the first time that preventing REST accumulation reduces neuronal cell death and ameliorates ALS symptoms, also through the activation of the necroptotic cell death pathway. Since no effective therapies for ALS are currently known, pharmacological inhibition of REST might represent a promising and innovative strategy to investigate for the treatment of ALS.