Background: The incidence of anterior cruciate ligament (ACL) injuries among adolescent athletes is steadily increasing. Identification of the highest risk sports for ACL injuries by sex and competitive setting (ie, practice vs match) is important for targeting injury prevention programs. Purpose: To identify the risk of ACL injuries in adolescent athletes by sport, sex, and setting across a variety of common US and international sports. Study Design: Meta-analysis. Methods: Essentially, 3 online databases (PubMed, Embase, and Cochrane Library) were searched for all studies of ACL injuries per athlete-exposure (AE) or hours of exposure in adolescent athletes. Injuries were then pooled and incidence rates (IRs) reported per 1000 AEs or hours of exposure, with the relative risk (RR) of injuries calculated for sex-comparable sports. IRs per competitive setting (match vs practice) were also calculated. Results: A total of 1235 ACL injuries over 17,824,251 AEs were identified (IR, 0.069 [95% CI, 0.065-0.074]), with 586 of these injuries in girls across 6,986,683 AEs (IR, 0.084 [95% CI, 0.077-0.091]) versus 649 injuries in boys over 10,837,568 AEs (IR, 0.060 [95% CI, 0.055-0.065]). Girls had a higher overall rate of ACL injuries (RR, 1.40 [95% CI, 1.25-1.57]), with the most disproportionate risk observed in basketball (RR, 4.14 [95% CI, 2.98-5.76]). The risk of ACL injuries by sex was highest in girls’ soccer (IR, 0.166 [95% CI, 0.146-0.189]) and boys’ football (IR, 0.101 [95% CI, 0.092-0.111]). ACL injuries were over 8 (RR, 8.54 [95% CI, 6.46-11.30]) and 6 (RR, 6.85 [95% CI, 5.52-8.49]) times more likely to occur in a match versus a practice setting for female and male athletes, respectively. Conclusion: The risk of ACL injuries overall approached nearly 1 per 10,000 AEs for female athletes, who were almost 1.5 times as likely as male athletes to suffer an ACL injury across all adolescent sports. A multisport female athlete was estimated to have a nearly 10% risk of ACL injuries over her entire high school or secondary school career. Specifically, male and female adolescents playing soccer, basketball, lacrosse, and football appeared at particular risk of injuries, a finding that can be used to target an injury intervention.