Exercise has anti-inflammatory properties useful to prevent and treat some chronic diseases. The expression of activating transcription factor 3 (ATF3) increases in skeletal muscle after exercise. In many tissues, ATF3 regulates the inflammatory response. Whether ATF3 contributes to the anti-inflammatory properties of exercise in skeletal muscle was unknown. To understand the role of ATF3 in skeletal muscle, we used a mutant mouse model unable to express ATF3 (ATF3-KO). We found that the expression of some inflammation-related genes was higher in ATF3-KO than control mice postexercise. ATF3-KO mice also had an impaired molecular adaptation to training in skeletal muscle. Our data suggest ATF3 is an important regulator of the inflammation postexercise, which could influence training adaptation in skeletal muscle. Since inflammation is involved in the pathogenesis of many diseases, the identification of ATF3 as an exercise-induced anti-inflammatory factor is relevant for future studies.