Spinal muscular atrophy (SMA) is caused by homozygous loss of human SMN1 (survival motor neuron 1). Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, called SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of SMN isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. We show that this interaction is conserved from fly to human, and that SCFSlmb interacts with a phospho-degron embedded within the SMN YG-box self-oligomerization domain. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Furthermore, overexpression of SMNΔ7S270A, but not wild-type SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the SCFSlmb degron is largely exposed when SMN is monomeric, whereas it is sequestered when SMN forms higher-order multimers. SMN stability is thus regulated by self-oligomerization, providing an elegant mechanism for controlling functional activity.