The stress experienced by the tibia has contributions from the forces and moments acting on the tibia. We sought to quantify the influence of running grade on internal tibial forces and moments. Seventeen participants ran at 3.33 m/s on an instrumented treadmill at 0 deg, ±5 deg, and ±10 deg while motion data were captured. Ankle joint contact force was estimated from an anthropometrically-scaled musculoskeletal model using inverse dynamics-based static optimization. Internal tibial forces and moments were quantified at the distal 1/3rd of the tibia, by ensuring static equilibrium with all applied forces and moments. Downhill running conditions resulted in lower peak internal axial force (range of mean differences: −9% to −16%, p < 0.001), lower peak internal anteroposterior force (−14% to −21%, p < 0.001), and lower peak internal mediolateral force (−14% to −15%, p < 0.001), compared to 0 deg and +5 deg. Furthermore, downhill conditions resulted in lower peak internal mediolateral moment (−11%to −21%, p < 0.001), lower peak internal anteroposterior moment (−13% to −14%, p < 0.001), and lower peak internal torsional moment (−9% to −21%, p < 0.001), compared to 0 deg, +5 deg, and +10 deg. The +10 deg condition resulted in lower peak internal axial force (−7% to −9%, p < 0.001) and lower peak internal mediolateral force (−9%, p = 0.004), compared to 0 deg and +5 deg. These findings suggest that downhill running may be associated with lower tibial stresses than either level or uphill running.