Skeletal muscle normally exhibits robust regenerative potential in youth; however, myogenic activity declines with age, resulting in defective muscle repair after injury. In this study, we identified signaling pathways in mouse muscle stem cells that are altered with aging and contribute to age-dependent decline in muscle regenerative potential. By analyzing the transcriptional profile of highly purified muscle satellite cells, we identified a unique set of genes whose expression changes with chronological time. This set contains genes regulating inflammatory processes, cell adhesion and matrix interactions, proteolysis, extracellular matrix remodeling, skeletal muscle development, cancer and connective tissue disorders. Ingenuity Pathway Analysis (IPA) of these transcripts indicated a central role for the NF-κB pathway in muscle satellite cell dysfunction. In addition, we noted altered expression of extracellular matrix genes, a signature that could be linked to changes in TGF-β-like signaling activity. Pharmacological modulation of either the NF-κB or TGF-β-like signaling pathways with small molecule inhibitors targeting IKK2 kinase or ALK4/5 receptor-like kinase enhanced regenerative potential in aged muscle, altering both the kinetics and magnitude of the response. These results identify key pathways underlying age-related muscle dysfunction and demonstrate the potential therapeutic relevance of small molecules that target them.