To uncover potential factors that may be involved in the impaired regenerative capacity of aged skeletal muscle, we comprehensively assessed the molecular stress response following muscle damage in old and young individuals. 10 young (22.7 ± 2.25 yrs) and 8 physically active old (70.9 ± 7.5 yrs) subjects completed a bout of 300 lengthening contractions (LC), and muscle biopsies were taken pre-exercise and at 3, 24, and 72 h post-LC. Both age groups performed the same amount of work during LC, with the old group displaying a resistance to LC-induced fatigue during the exercise. Muscle damage was evident by soreness and losses in isokinetic force and power production, though older subjects experienced reduced force and power losses relative to the young group. The acute extracellular matrix (ECM) response was characterized by substantial increases in the glycoproteins tenascin C and fibronectin in the young, which were blunted in the old muscle following damage. Old muscle displayed a generally heightened and asynchronous inflammatory response compared to young muscle, with higher expression of MCP-1 that appeared at later time points, and increased NF-κb activity. Expression of the stress-related MAPKs P38 and JNK increased only in the old groups following muscle damage. In summary, aberrations appear in the inflammatory, ECM and MAPK responses of aged skeletal muscle following damaging LC, each of which may individually or collectively contribute to the deterioration of muscle repair mechanisms that accompanies aging.