ObjectiveInvestigate sex/gender differences in self-reported activity and knee-related outcomes after anterior cruciate ligament (ACL) injury.DesignSystematic review with meta-analysis.Data sourcesSeven databases were searched in December 2021.Eligibility criteriaObservational or interventional studies with self-reported activity (including return to sport) or knee-related outcomes after ACL injury.ResultsWe included 242 studies (n=123 687, 43% females/women/girls, mean age 26 years at surgery). One hundred and six studies contributed to 1 of 35 meta-analyses (n=59 552). After ACL injury/reconstruction, very low-certainty evidence suggests females/women/girls had inferior self-reported activity (ie, return to sport, Tegner Activity Score, Marx Activity Scale) compared with males/men/boys on most (88%, 7/8) meta-analyses. Females/women/girls had 23%–25% reduced odds of returning to sport within 1-year post-ACL injury/reconstruction (12 studies, OR 0.76 95% CI 0.63 to 0.92), 1–5 years (45 studies, OR 0.75 95% CI 0.69 to 0.82) and 5–10 years (9 studies, OR 0.77 95% CI 0.57 to 1.04). Age-stratified analysis (<19 years) suggests female athletes/girls had 32% reduced odds of returning to sport compared with male athletes/boys (OR 0.68, 95% CI 0.41 to 1.13, I20.0%). Very low-certainty evidence suggests females/women/girls experienced inferior knee-related outcomes (eg, function, quality of life) on many (70%, 19/27) meta-analyses: standardised mean difference ranging from −0.02 (Knee injury and Osteoarthritis Outcome Score, KOOS-activities of daily living, 9 studies, 95% CI −0.05 to 0.02) to −0.31 (KOOS-sport and recreation, 7 studies, 95% CI −0.36 to –0.26).ConclusionsVery low-certainty evidence suggests inferior self-reported activity and knee-related outcomes for females/women/girls compared with males/men/boys after an ACL injury. Future studies should explore factors and design targeted interventions to improve outcomes for females/women/girls.PROSPERO registration numberCRD42021205998.