Atrophy is thought to be a primary mode of muscle loss in neuromuscular injuries. The differential effects of central and peripheral injuries on atrophy and degeneration/regeneration in skeletal muscle tissue have not been well described. This study investigated skeletal muscle atrophy and degeneration/regeneration in an animal model of traumatic brain injury (TBI). Eight 8-month-old wild-type C57BL6 mice underwent either a sham craniotomy or TBI targeting the motor cortex. Atrophy (fiber area; FA) and degeneration/regeneration (centralized nuclei proportions; CN) of the soleus and tibialis anterior (TA) muscles were measured 2 months post-injury. Injured soleus FAs were smaller than sham soleus (p = 0.02) and injured TA (p < 0.001). Mean CNs were higher in the TBI-injured TA than in other muscles. Differential TBI-induced atrophy and degeneration/regeneration in lower limb muscles suggests that muscle responses to cortical injury involve more complex changes than those observed with simple disuse atrophy.