Objectives American football continues to be a popular and rapidly growing sport among both males and females, with relatively little research concerning injuries for the latter - especially in the youth population. The current study aims to evaluate the differences in the epidemiology of injured body parts and injury diagnoses between youth male and female American football players. Methods Injury data for male and female American football players were collected over a 10- year period from the National Electronic Injury Surveillance System (NEISS) and retrospectively reviewed. Patients between ages 4 and 18 years with a medical injury/condition related to American football were included. Descriptive analyses were performed for all data including injured body parts, injury diagnoses and setting, demographics, and medical disposition. Odds ratio (OR), 95% CI, and p-values (p < 0.05) were used for the statistical significance between the two groups. Results A total of 82,174 American football injuries were found in the NEISS dataset, 95.0% of which were male with a mean age of 13.0 +/- 2.9 years. The most injured body parts were the head (17.7%), finger (13.8%), knee (9.2%), shoulder (8.7%), and ankle (8.0%). The most prevalent injury diagnoses were fractures (24.5%), sprains/strains (22.7%), contusions/bruises (12.2%), concussions (9.8%), and internal injuries (7.1%). Males were more likely to suffer head (OR = 1.32, p < 0.001), knee (OR = 1.23, p < 0.001) and shoulder (OR = 2.19, p < 0.001) injuries and females suffered more finger (OR = 3.22, p < 0.001) and ankle (OR = 1.25, p < 0.001) injuries. Males were more likely to suffer concussions (OR = 1.50, p < 0.001) whereas females sustained more sprains/strains (OR = 1.32, p < 0.001). Conclusion Youth male American football players had a greater likelihood of sustaining concussions and head, knee, and shoulder injuries, whereas females were more likely to have sprains/strains, finger, and ankle injuries. Future studies are warranted to further explore how these differences may be attributed to play style and sex-based physiologic and development differences.