Abstract: Kraemer, WJ, Looney, DP, Martin, GJ, Ratamess, NA, Vingren, JL, French, DN, Hatfield, DL, Fragala, MS, Spiering, BA, Howard, RL, Cortis, C, Szivak, TK, Comstock, BA, Dunn-Lewis, C, Hooper, DR, Flanagan, SD, Volek, JS, Anderson, JM, Maresh, CM, and Fleck, SJ. Changes in creatine kinase and cortisol in national collegiate athletic association division I American football players during a season. J Strength Cond Res 27(2): 434–441, 2013—The purpose of this study was to track creatine kinase (CK) and serum cortisol over an American college football season starting with the preseason practice. A secondary purpose was to observe changes in basic clinical chemistries. Twenty-two National Collegiate Athletic Association Division I football players (age: 20.4 ± 1.1 years, height: 188.27 ± 8.3 cm, weight: 115.8 ± 29.7 kg) volunteered to participate in this study. Each of the players had participated in the summer strength and conditioning supervised program. Resting blood samples were obtained just before the start of preseason practice (T-1), 2 weeks later (T-2), and the day after game 2 (T-3), game 4 (T-4), game 6 (T-5), and game 9 (T-6) of a 12-game season. Creatine kinase, a panel of clinical chemistries, cortisol, and testosterone were assayed at each time point. No significant changes in CK concentrations were observed over the season with peak values of each range ≤1,070.0 IU·L−1, but the largest range was observed at T-6 after game 9 (119–2,834 IU·L−1. The analysis of covariance analysis demonstrated that the number of plays in the ninth game (T-6) explained the magnitude of the changes in CK. No changes in serum cortisol concentrations were observed yet, again large variations existed with peak values of each range ≤465.0 nmol·L−1. Clinical chemistries showed various significant changes from T-1, but none were considered clinically relevant changes for any player over the time course of the study. In conclusion, the strength and conditioning program before preseason camp or the structure of summer camp practices and the in-season strength and conditioning appeared to mute muscle damage and the stress response of cortisol. Such data demonstrate that changes in muscle damage and adrenal cortical stress over the season are minimal, yet large individual variations can be observed. Management of these variables appears to be related to optimal strength and conditioning and sports medicine programs. Thus, the greater concerns for student-athlete safety in the sport of American football are related to preventing sudden death, traumatic injury, and managing concussion syndromes.