Damage to the microtubule lattice, which serves as a rigid cytoskeletal backbone for the axon, is a hallmark mechanical initiator of pathophysiology after concussion. Understanding the mechanical stress transfer from the brain tissue to the axonal cytoskeleton is essential to determine the microtubule lattice's vulnerability to mechanical injury. Here, we develop an ultrastructural model of the axon's cytoskeletal architecture to identify the components involved in the dynamic load transfer during injury. Corroborative in vivo studies were performed using a gyrencephalic swine model of concussion via single and repetitive head rotational acceleration. Computational analysis of the load transfer mechanism demonstrates that the myelin sheath and the actin/spectrin cortex play a significant role in effectively shielding the microtubules from tissue stress. We derive failure maps in the space spanned by tissue stress and stress rate to identify physiological conditions in which the microtubule lattice can rupture. We establish that a softer axonal cortex leads to a higher susceptibility of the microtubules to failure. Immunohistochemical examination of tissue from the swine model of single and repetitive concussion confirms the presence of postinjury spectrin degradation, with more extensive pathology observed following repetitive injury. Because the degradation of myelin and spectrin occurs over weeks following the first injury, we show that softening of the myelin layer and axonal cortex exposes the microtubules to higher stress during repeated incidences of traumatic brain injuries. Our predictions explain how mechanical injury predisposes axons to exacerbated responses to repeated injuries, as observed in vitro and in vivo.