Injuries to the knee anterior cruciate ligament (ACL) are common, with a known but poorly understood association with intrinsic and extrinsic risk factors. Some of these factors are enzymatically or mechanically mediated, creating acute focal injuries that may cause significant ligament damage. Understanding the relationship between the basic molecular structure and external loading of the ACL requires a hierarchical connection between the two levels. In the present study, a multi-domain frame was developed connecting the molecular dynamics of the collagen networks to the continuum mechanics of the ACL. The model was used to elucidate the effect of the two possible collagen degradation mechanisms on the aggregate ACL behaviour. Results indicated that collagen content and ACL stiffness were reduced significantly, regardless of the degradation mechanism. Furthermore, the volumetric degradation at the molecular level had a devastating effect on the mechanical behaviour of the ACL when it was compared with the superficial degradation. ACL damage initiation and propagation were clearly influenced by collagen degradation. To summarise, the new insights provided by the predicted results revealed the significance of the collagen network structural integrity to the aggregate mechanical response of the ACL and, hence, underlined the biomechanical factors that may help develop an engineering-based approach towards improving the therapeutic intervention for ACL pathologies.