Aging decreases muscle mass, strength, and functional capacity. High-salt stress seems to promote muscle aging and decrease lifespan. However, exercise delays muscle aging and increases longevity, and it may protect muscle from rapid aging induced by high-salt intake (HSI), but the molecular mechanisms are poorly understood. In this study, the flies were fed a high-salt diet and trained to exercise. Muscle CG2196 (salt) gene and dSir2 gene were over-expressed by building mef2-gal4/UAS system. The results showed that both physical exercise and muscle dSir2 gene overexpression prevented HSI-induced and muscle salt overexpression-induced accelerated age-related decline of climbing index, climbing endurance, muscle NAD+ level, SOD activity level, dSir2 expression, and dFOXO expression, and they also prevented HSI-induced and muscle salt overexpression-induced accelerated age-related increase in muscle ROS level, MDA level, and salt gene expression. Physical exercise improved lifespan decrease induced by HSI and muscle salt overexpression. Therefore, current results indicated that high-salt stress accelerated muscle aging by decreasing muscular NAD+/dSir2/dFOXO pathway activity and increasing oxidative stress. Physical exercise protected muscle from accelerated aging induced by high-salt stress through activating muscle NAD+/dSir2/dFOXO pathway and enhancing muscle oxidation resistance. The combination of exercise and muscle dSir2 overexpression had the best protective effect on muscle aging and lifespan in flies.