Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by spinal and brainstem motor neuron (MN) loss and skeletal muscle paralysis. Currently there is no effective treatment other than supportive care to ameliorate the quality of life of SMA patients. Some studies have reported that physical exercise is potentially beneficial in SMA by improving muscle strength and motor function. The AMP-activated protein kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) has been reported to be an exercise mimetic agent that is able to regulate muscle metabolism and increase endurance both at rest and during exercise. Chronic AICAR administration has been shown to ameliorate the dystrophic muscle phenotype and motor behavior in the mdx mouse, a model of Duchenne muscular dystrophy. Here, we investigated whether chronic AICAR treatment was able to elicit beneficial effects on motor abilities and neuromuscular histopathology in a mouse model of severe SMA (the SMNΔ7 mouse). We report that AICAR improved skeletal muscle atrophy and structural changes found in neuromuscular junctions of SMNΔ7 animals. However, although AICAR prevented the loss of glutamatergic excitatory synapses on MNs, this compound was not able to mitigate MN loss or the microglial and astroglial reaction occurring in the spinal cord of diseased mice. Moreover, no improvement in both survival and motor performance was seen in SMNΔ7 animals treated with AICAR. The beneficial effects of AICAR in SMA found in our study are SMN-independent, since no changes in the expression of this protein were seen in the spinal cord and skeletal muscle of diseased animals treated with this compound.