Subconcussive head impacts (SHI), defined as impacts to the cranium that do not result in concussion symptoms, are gaining traction as a major public health concern. The contribution of physiological factors such as physical exertion and muscle damage to SHI-dependent changes in neurological measures remains unknown. A prospective longitudinal study examined the association between physiological factors and SHI kinematics in 15 high school American football players over one season. Players wore a sensor-installed mouthguard for all practices and games, recording frequency and magnitude of all head impacts. Serum samples were collected at 12 time points (pre-season, pre- and post-game for five in-season games, and post-season) and were assessed for an isoenzyme of creatine kinase (CK-MM) primarily found in skeletal muscle. Physical exertion was estimated in the form of excess post-exercise oxygen consumption (EPOC) from heart rate data captured during the five games. Mixed-effect regression models indicated that head impact kinematics were significantly and positively associated with change in CK-MM but not EPOC. There was a significant and positive association between CK-MM and EPOC. These data suggest that when examining SHI, effects of skeletal muscle damage should be considered when using outcome measures that may have an interaction with muscle damage.