Background: The risk of injury associated with American football is significant, with recent reports indicating that football has one of the highest rates of all-cause injury, including concussion, of all major sports. There are limited studies examining risk factors for injuries in the National Football League (NFL). Purpose: To identify risk factors for NFL concussions and musculoskeletal injuries. Study Design: Case-control study; Level of evidence, 3. Methods: Injury report data were collected prospectively for each week over the 2012-2013 and 2013-2014 regular seasons for all 32 teams. Poisson regression models were used to identify the relationship between predetermined variables and the risk of the 5 most frequent injuries (knee, ankle, hamstring, shoulder, and concussion). Results: A total of 480 games or 960 team games (TGs) from the 2012-2013 and 2013-2014 regular seasons were included in this study. A trend to an increasing risk of concussion and TG ankle injury with decreasing mean game-day temperature was observed. The risk of TG concussion (incidence rate ratio [IRR], 2.16; 95% CI, 1.35-3.45; P = .001) and TG ankle injury (IRR, 1.48; 95% CI, 1.10-1.98; P = .01) was significantly greater for TGs played at a mean game-day temperature of 9.7 degrees C (49.5 degrees F) compared with a mean game-day temperature of 21.0 degrees C (69.8 degrees F). The risk of TG shoulder injury was significantly increased for TGs played on grass surfaces (IRR, 1.36; 95% CI, 1.02-1.81; P = .038) compared with synthetic surfaces. The risk of TG injury was not associated with time in season, altitude, time zone change prior to game, or distance traveled to a game. Conclusion: This study evaluated extrinsic risk factors for injury in the NFL. A hazardous association was identified for risk of concussion and ankle injury with colder game-day temperature. Further research should be conducted to substantiate this relationship and its potential implication for injury prevention initiatives.