This review examines a mechanism for the initiation of osteoarthritis after anterior cruciate ligament (ACL) injury by considering the relationship between reported ambulatory changes after ACL injury, cartilage adaptation to load, and the association between cartilage loads during walking and regional variations in cartilage structure and biology. Taken together, these observations suggest that cartilage degeneration after ACL injury could be caused by a kinematic gait change that shifts ambulatory loading applied to cartilage. Such a shift may cause regions of cartilage to become newly loaded, be subjected to altered levels of compression and tension, or become unloaded. The metabolic sensitivity of chondrocytes to such changes in their mechanical environment, combined with the low adaptation potential of mature cartilage, could lead to cartilage degeneration and premature osteoarthritis after ACL injury. This proposed mechanism demonstrates the value of using the ACL injury model to understand the relationship between mechanics and biology, as well as helping to explain the importance of restoring normal ambulatory kinematics after ACL injury to avoid premature osteoarthritis.