Anterior cruciate ligament (ACL) disruption is a common injury that is detrimental to an athlete’s quality of life. Determining the mechanisms that cause ACL injury is important in order to develop proper interventions. This study was conducted to provide insight into the specific knee orientations associated with ACL injuries. A failure locus for the ACL was developed by simulating multiple loading scenarios using a 3-D finite element analysis (FEA) model of the knee. The results indicated varus and valgus were more dominant to the ACL injury compared to femoral rotation. The order of MCL failure, ACL failure, and maximum meniscus stress was also determined with respect to time during loading. The results of this study could be used to develop training programs focused on the avoidance of the described combination of movements, which may lead to ACL injury.