The purpose of this study was to examine markers of skeletal muscle tissue damage and circulating anabolic and catabolic hormones to gain insight into the recovery process from Friday until Monday, when a new practice week begins. Twenty-eight National Collegiate Athletic Association Division I football players gave consent to participate in the investigation in the ninth game of the season. Sixteen players started the game and played the entire game (PL), and 12 others did not play and were on the bench during the game (DNP). Each player had fasted blood samples obtained at the same time of day between 1000 and 1200 hours the day before the game (Friday; T1), 18-20 hours after the game (Sunday; T2), and then 42-44 hours after the game (Monday; T3). Blood samples were analyzed for concentrations of creatine kinase (CK), lactate dehydrogenase (LDH), myoglobin, testosterone, and cortisol. The PL players showed significantly (p T1 and T3), myoglobin (T2 > T1 and T3), and LDH (T2 > T1). In contrast, DNP players showed significant differences in cortisol (T3 <T1 and T2) and testosterone:cortisol (T3 > T1). Few changes were observed in testosterone and cortisol changes, indicating stability of the anabolic/catabolic hormones. In conclusion, these data indicate that participation in a college football game late in the season results in some degree of tissue damage but with minimal hormonal responses, which seem to have stabilized at resting concentrations without predominance of cortisol's catabolic presence. As previously noted in the literature, some type of "contact adaptation" to the season may have occurred with regard to tissue damage responses. However, by the ninth game of a season, players do carry soft tissue damage levels above resting ranges into subsequent games, indicating that recovery should be monitored, with coaches being careful with scheduling scrimmage and full-contact drills. How such data implicate overuse injuries remains unclear, considering that hormonal status in this study was highly stable, with catabolic influences minimized by the high level of athlete conditioning. These data again support that high-level conditioning can stabilize anabolic and catabolic hormonal signals and limit acute soft tissue injury, making cerebral concussion (acute and chronic) and traumatic injury the biggest threats to a student-athlete's health and well-being during an American football game.