AMP-activated protein kinase (AMPK) is a primary regulator of cellular metabolism. Recent studies have revealed that AMPK also mediates the maintenance and plasticity of α-motoneurons, the neuromuscular junction, and skeletal muscle. Furthermore, AMPK stimulation by either genetic, pharmacological, or physiological approaches elicits beneficial phenotypic remodeling in neuromuscular disorders (NMDs). Here, we review the role of AMPK as a governor of neuromuscular biology, and present evidence for AMPK as an effective molecular target for therapeutic pursuit in the context of the most prevalent NMDs, including Duchenne muscular dystrophy, spinal muscular atrophy, and myotonic dystrophy type 1. This information may be useful for engineering AMPK-targeted pharmacological- or lifestyle-based strategies to treat disorders of the neuromuscular system.