Obesity is increasing rapidly worldwide, accompanied with many complications including impaired muscle regeneration. Obese condition is known to inhibit AMP-activated protein kinase (AMPK) activity in multiple tissues. We hypothesized that the loss of AMPK activity is a major reason for the hampered muscle regeneration in obese subjects. We found that obesity inhibited AMPK activity in regenerating muscle, which was associated with impeded satellite cell activation, and impaired muscle regeneration. To test the mediatory role of AMPKα1, we knocked out AMPKα1 and found that both proliferation and differentiation of satellite cells are reduced following injury and muscle regeneration was severely impeded, reminiscent to hampered muscle regeneration seen in obese subjects. Transplanted satellite cells with AMPKα1 deficiency had severely impaired myogenic capacity in regenerating muscle fibers. Finally, we found attenuated muscle regeneration in obese mice was rescued by AICAR, a drug specifically activating AMPK. On the other hand, AICAR treatment failed to improve muscle regeneration in obese mice with satellite cell-specific AMPKα1 knockout, demonstrating the importance of AMPKα1 in satellite cell activation and muscle regeneration. In summary, AMPKα1 is a key mediator linking obesity and impaired muscle regeneration, providing a convenient drug target to facilitate muscle regeneration in obese populations.