Neurological disorders remain the world’s leading cause of disability and the second leading cause of death worldwide. Over the past decade, there has been significant improvements in technological breakthroughs for brain imaging and therapeutics. However, the treatments of most CNS-related disorders remain ineffective. This is not due to the lack of drug potency but rather the inability of the drugs to reach their CNS target due to the presence of a formidable blood-brain barrier (BBB) that impedes the CNS entry of most neurotherapeutics. In this study, we focused on developing BBB-crossing peptides as delivery vectors for therapeutic antisense oligonucleotides. We investigated the ability of various peptides for delivery of a phosphorodiamidate morpholino oligonucleotide (PMO) into the CNS following peripheral injection. We identified peptides (20 to 35-mer) derived from receptor-binding domain of Apoliprotein E that were able to deliver PMO (~6.5 kDa) into the CNS and significantly increased (~30-fold) functional survival motor neuron-2 level in a mouse model of spinal muscular atrophy (SMA). Treatment of newborn SMA mice (with an average survival of 14 days) with peptide-PMO conjugates resulted in a significant increase in the average lifespan (78 days) with normal weight gain and muscle strength. In this study, we have shown that peptides are able to safely deliver large bio-cargoes into the CNS with functional effect in SMA mice. Therefore, the peptide-based delivery platform has a great potential and can be applied to the delivery of a wide range of therapeutics to treat neurodegenerative diseases, brain cancers and stroke, and can also be used to deliver neuroimaging agents for the diagnosis of CNS diseases.