Skeletal muscle function and viability are dependent upon intact innervation. Peripheral nerve injury and muscle denervation cause muscle atrophy. Time to re‐innervation is one of the most important determinants of functional outcome. While short‐term denervation can result in nearly fully reversible changes in muscle mass, prolonged denervation leads to irreversible muscle impairment from profound atrophy, myocyte death and fibrosis. We performed transcriptional profiling to identify genes that were altered in expression in short‐term (1 month) and long‐term (3 month) denervated muscle and validated the microarray data by RT‐PCR and Western blotting. Genes controlling cell death, metabolism, proteolysis, stress responses and protein synthesis/translation were altered in expression in the denervated muscle. A differential pattern of expression of genes encoding cell cycle regulators and extracellular matrix components was identified that correlated with the development of irreversible post‐denervation changes. Genes encoding mediators of protein degradation were differentially expressed between 1 and 3 month denervated muscle suggesting different signaling networks are recruited over time to induce and maintain muscle atrophy. Understanding of the timing and type of pathological processes that are triggered by denervation may allow the design of interventions that delay or protect muscle from loss of nerve function.