Background: Orthopaedic injuries of National Football League (NFL) players can have a deleterious effect on their health, with minimal to no high-level evidence on the management of these injuries. Purpose: To summarize all data published between January 1980 and March 2018 on orthopaedic injuries experienced by NFL candidates and professional players in the NFL. Study Design: Systematic review; Level of evidence, 4. Methods: A literature search of studies examining orthopaedic injuries in the NFL was performed through the PubMed, Embase, and CINAHL databases. The review included studies of orthopaedic injuries in college football recruits attending the NFL Combine as well as professional NFL players. Excluded were studies of nonorthopaedic injuries, such as concussions, traumatic brain injury, facial injuries, and vascular injuries, as well as case reports. Results: A total of 147 articles met the inclusion criteria and were divided into 11 topics based on anatomic site: general (16%), spine (13%), shoulder (13%), elbow (3%), hand and wrist (3%), trunk (0.7%), hip and pelvis (7%), thigh (3%), knee (24%), ankle (5%), and foot (12%). Of these studies, 74% were of level 4 evidence. Most studies obtained data from the NFL Combine database (26%), by searching the internet (24%), and via the NFL Injury Surveillance System (22%). Studies using internet search methods to identify injuries consistently found fewer participants than studies using the NFL Injury Surveillance System. Conclusion: This systematic review provides National Collegiate Athletic Association and NFL team physicians with a single source of the most current literature regarding orthopaedic injuries in NFL players. Most research was published on knee, spine, shoulder, and foot injuries and consisted of level 4 evidence. A substantial portion of the published literature was based on data obtained from internet searches and may not accurately represent the NFL population.