Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in the survival motor neuron 1 ( SMN1 ) gene. SMA is characterised by alpha motor neuron loss in the spinal cord and subsequent muscle atrophy. There are currently three approved SMN-directed therapies for SMA patients. While these therapies have transformed what was once a life-limiting condition into one that can be managed and even improved, they are unfortunately not cures, highlighting the need for additional supporting second-generation therapies. These should not only target the neuromuscular system but also peripheral and metabolic perturbations that are present in both SMA models and patients. Krüppel-like factor 15 (Klf15) is a transcription factor that maintains metabolic homeostasis, is involved in the glucocorticoid-glucocorticoid receptor (GR) signalling pathway and is dysregultated in several peripheral and metabolic tissues in SMA mice. Here, we used murine and human cellular models as well as SMA mice and Caenorhabditis Elegans (C. elegans) to assess the therapeutic potential of reducing Klf15 activity with mifepristone, a glucocorticoid antagonist, combined with a SMN-targeted gene therapy. We report that mifepristone reduces Klf15 expression across several in vitro models, ameliorates neuromuscular pathology in SMA smn-1(ok355) C. elegans and improves survival of SMA Smn 2B/- mice. Furthermore, we show that combining mifepristone with an approved SMN-directed gene therapy (scAAV9- SMN1 ) results in improved tissue- and sex-specific responses to treatment. Our study demonstrates that a multi-tissue targeting SMN-independent drug, alone and in combination with an approved SMN-dependent therapy, has the potential to improve SMA disease pathology.