The purpose of this study was to examine the effect of depression and anxiety symptoms on the prospective injury hazard among collegiate American football athletes. An open cohort of intercollegiate football players (n = 330) from two Division I universities were enrolled and followed during the 2008-2010 seasons. Of 330 enrolled players, 121 (36.7%) sustained at least one injury during the participation period. A total of 66 players (20.0%) reported experiencing symptoms of depression and 109 (33.0%) reported anxiety at the time of enrollment. Depression was associated with increased likelihood of injury (hazard ratio (HR) = 1.81, 95% confidence interval (CI): 1.65, 1.98). Anxiety had an opposite effect and was protective from injury hazard (HR= 0.79, 95% CI: 0.66, 0.93). Football players who experienced depression at enrollment were 10% less likely to remain injury-free than those who did not have depressive symptoms. Evidence from this study suggests injury prevention efforts need to include strategies targeting psychological risk factors.