Objectives: The National Football League, among the most popular team sports in the United States, carries an injury incidence that is higher than that of other collision sports, such as rugby and ice hockey. Considerable research has been undertaken to investigate the etiology of injuries in the NFL and has identified numerous risk factors on the level of individual games, including playing surface and gameday weather conditions; additionally, one study has found that concussion risk is not affected by scheduling variation, such as overseas games and bye week timing. However, there is currently no data that reports the effects of scheduling variation over the course of a season on musculoskeletal injury incidence. The purpose of this retrospective study was to describe the relationship between scheduling factors and injury rates among professional athletes in the NFL. It was hypothesized that higher cumulative travel distance, playing overseas games, an early season bye week, and an expansion of the regular season would be associated with higher injury rates. Methods: The current study was a descriptive epidemiological study that retrospectively reviewed all injuries that occurred in the five NFL seasons from the 2017-2018 season through the 2021-2022 season. Injury data and travel distances were extracted from publicly available sources and injury reports were cross-referenced to verify injury data. Injury rates were calculated per 1,000 athletic exposures (AEs). Results: In 1,216 regular season games in the five NFL seasons, 4,378 injuries were reported for an average injury rate per year of 34.42 injuries per 1,000 AEs. Cumulative team travel distance did not significantly predict injury rates (Figure 1). There was not a statistically significant difference in injury rates between NFL teams that did (19.3 per 1,000 AEs) versus did not play a game overseas (19.3 per 1,000 AEs) (Figure 2). There was not a statistically significant difference in injury rates or the number of players on the injured reserve list between the various bye weeks. There was not a statically significant difference in injury rates between the new 17-game regular season (18.4 per 1,000 AEs) versus the previous four 16-game regular seasons (19.7 per 1,000 AEs) (Figure 3). However, NFL teams that did not qualify for the playoffs had a significantly higher injury rate (19.9 per 1,000 AEs) versus teams that did qualify for the playoffs (18.4 per 1,000 AEs). Also, NFL teams that did not qualify for the playoffs had a significantly higher number of players on the injured reserve list (8.0 per 1,000 AEs) versus teams that qualified for the playoffs (6.8 per 1,000 AEs) (Figure 4). Conclusions: Over five NFL seasons, increased cumulative travel distance, playing a game overseas, and having an early season bye week were not associated with increased injury rates in professional football players. The addition of one regular season game, from 16 to 17 during the 2020 season, was not associated with an increased injury rate. However, not qualifying for post-season play was associated with an increased injury rate and an increase in the number of players on injured reserve. Overall, the analysis suggests that the analyzed parameters in the current NFL schedule were not risk factors for musculoskeletal injuries over the last five seasons; however, lack of regular season success may be associated with higher injury rates and more players on injured reserve.