Abstract: Spinal muscular atrophy (SMA) is a genetic disorder that primarily affects infants and leads to muscle weakness, atrophy, and paralysis. The main cause is the homozygous mutation or deletion of the SMN1 gene, resulting in inadequate levels of the survival motor neuron (SMN) protein. Approved treatments focus on restoring SMN levels through various approaches, but there is a need for “SMN-independent” therapies that target other pathological processes. Skeletal muscle is closely involved in SMA pathology, with impaired muscle function observed before motor neuron degeneration. Studies have revealed that SMN loss leads to skeletal muscle mitochondrial structural abnormalities, impaired respiration, and accumulation of reactive oxygen species. Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have emerged as a therapeutic option due to their regenerative and immunomodulatory capabilities, including the ability to replace dysfunctional mitochondria through transcellular exchange. Amniotic fluid stem (AFS) cells are considered a favorable source for stem cell therapy due to their unique properties. By transplantation of AFS cells in a mouse model of SMN loss in the skeletal muscle we could restore mitochondrial function and correct the muscle phenotypes of SMA. Utilizing stem cell therapies to restore mitochondrial function offers promising avenues for the treatment of SMA.