Exposure to game conditions and previous injury are known to increase the risk of injury, but little available evidence pertains to modifiable factors that may mediate dynamic control of body segments, such as core muscle endurance and neurocognitive capabilities. To identify potentially modifiable factors associated with the occurrence of a core or lower extremity sprain or strain during participation in football. Prospective cohort study. National Collegiate Athletic Association Division I Football Bowl Subdivision football program. All team members who participated for the duration of 1 season or both of 2 consecutive seasons (n = 142). Predictors of injury occurrence were derived from analysis of preparticipation data that included the results of front plank hold (FPH) and neurocognitive tests. Receiver operating characteristic analysis was used to establish binary classifications of injury risk. Logistic regression analyses were conducted to build multivariable injury-prediction models for optimal discriminatory power. Exceptionally good discrimination between injured and noninjured participants was provided by models that included the results of the FPH and ImPACT neurocognitive tests. A high level of exposure to game conditions and injury during the preceding year magnified the effects of other risk factors. A model for identifying players with an elevated risk for injury occurrence during both of 2 consecutive seasons included FPH ≤120 seconds, verbal memory score ≤87, composite reaction time ≥560 milliseconds, and starter status. Having ≥2 of the 4 risk factors demonstrated 44% sensitivity and 91% specificity, with an odds ratio = 8.40. Core muscle endurance and neurocognitive processes may both play important roles in generating anticipatory muscle stiffness during participation in collegiate football. These factors may be particularly important for players who sustained an injury during the previous year and those who have a high level of game exposure.