Bone strains in the lower extremity may be influenced by neuromuscular fatigue. In this study, we examined potential changes in finite element (FE) predicted tibial strains over the course of a fatiguing downhill-running protocol. Twelve physically active males ran for 30 min on an instrumented treadmill at a speed of 2.8 m s−1 and a grade of −11.3 deg. Motion capture and inverse-dynamic-based static optimization were used to estimate lower-extremity joint contact and muscle forces at the beginning, middle, and end stages of the downhill run. Finite element models of the tibia–fibula complex, from database-matched computed tomography images, were then used to estimate resulting 90th percentile strain (peak strain) and strained volume (volume of elements above 3000 με). In the fatigued state, peak ankle joint contact forces decreased an average of 8.1% (p < 0.002) in the axial direction, but increased an average of 7.7% (p < 0.042) in the anterior–posterior direction; consequently, finite element estimations of peak strain and strained volume were unaffected (p > 0.190). Although neuromuscular fatigue may influence ankle joint contact forces, it may not necessarily influence tibial strains due to the complex, and sometimes nonintuitive, relationship between applied load and resulting bone strain.