This study evaluated the effects of acetylsalicylic acid (ASA) on exercise-induced inflammatory response, muscle damage, and liver injury in rats. Wistar-Kyoto (WKY) rats were divided into six groups: control (C), exercise (E), C+20 mg ASA, E+20 mg ASA, C+100 mg/kg ASA, and E+100 mg ASA groups. ASA or a vehicle was orally administered through gavage 1 h before a treadmill test. Upon trial completion, blood was drawn at 1, 12, and 24 h for biochemical analysis, and livers were excised at 24 h for a histological assessment. Our results revealed that 100 mg/kg ASA significantly reduced interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the E groups; however, the IL-10 level was considerably increased. Moreover, aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and histological hepatic damage increased significantly in the E+100 mg ASA group compared with the corresponding changes in the E group. These results suggest that the prophylactic administration of particularly high-dose ASA alleviates exercise-induced inflammatory response but exacerbates liver injury.