Healthy behavioral patterns could modulate organ functions to enhance the body's immunity. However, how exercise regulates antiviral innate immunity remains elusive. Here, we found that exercise promotes type I interferon (IFN-I) production in the liver and enhances IFN-I immune activity of the body. Despite the possibility that many exercise-induced factors could affect IFN-I production, we identified Gpld1 as a crucial molecule, and the liver as the major organ to promote IFN-I production after exercise. Exercise largely loses the efficiency to induce IFN-I in Gpld1-/- mice. Further studies demonstrated that exercise-produced 3-hydroxybutanoic acid (3-HB) critically induces Gpld1 expression in the liver. Gpld1 blocks the PP2A-IRF3 interaction, thus enhancing IRF3 activation and IFN-I production, and eventually improving the body's antiviral ability. This study reveals that exercise improves antiviral innate immunity by linking the liver metabolism to systemic IFN-I activity and uncovers an unknown function of liver cells in innate immunity.