Eccentric muscle contraction can cause muscle damage, which reduces the efficiency of exercise. Previous evidence suggested that Sodium salicylate (SS) could improve the repair of aged muscle. This study intends to investigate whether SS can impact skeletal muscle damage caused by eccentric exercise. Eccentric treadmill exercise was performed to induce muscle damage in mice. Plasma levels of muscle damage markers were estimated. RT-qPCR was employed for detecting mRNA levels of proinflammatory mediators in murine gastrocnemius muscle. Immunofluorescence staining of laminin/DAPI was utilized for quantifying centrally nucleated myofibers in the gastrocnemius muscle. Western blotting was implemented to examine protein levels of mitsugumin 53 (MG53), matrix metalloproteinase (MMP)-2/9, and NF-κB signaling-related markers. SS administration reduced muscle damage marker production in the plasma and decreased the levels of proinflammatory mediators, MG53 and MMP-2/9 in mice after exercise. SS alleviated the severity of muscle damage in the gastrocnemius of mice after eccentric exercise. SS blocked NF-κB signaling pathway in the gastrocnemius muscle. SS administration ameliorates skeletal muscle damage caused by eccentric exercise in the mouse model.