Microgravity animal models have demonstrated corticospinal plasticity; however, little is understood of its functional significance. In this pilot study, we explored corticospinal plasticity in a bed rest model. We hypothesized that the lack of weight bearing would induce cortical reorganization correlating with performance. Four subjects underwent functional MRI (fMRI), transcranial magnetic stimulation (TMS), and functional mobility testing (FMT) before and after 90 d of bed rest. Recruitment curves (RC) were created by measuring motor evoked potentials over a range of TMS intensities with changes in the slope of the RC reflecting changes in corticospinal excitability. Significant leg RC slope decreases were observed on post-bed rest day 1 (P1) (t(2805) = -4.14, P < 0.0001), P2 (t(2805) = -6.59, P < 0.0001), P3 (t(2805) = -6.15, P < 0.0001), P5 (t(2805) = -7.93, P <0.0001), P8 (t(2805) = -3.30, P = 0.001), and P12 (t(2805)= -3.33, P = 0.0009), suggesting a group decrease in corticospinal excitability in the immediate post-bed rest period with recovery approaching baseline over the following 2 wk. Significant effects were observed for hand RC slopes only for P2 (t(2916) = 1.97, P = 0.049), P3 (t(2916) = -2.12, P = 0.034), and P12 (t(2916) = -2.19, P = 0.029); no significant effects were observed for days P0 (t(2916) = -1.32, ns), P1 (t(2916) = 1.00, ns), P5 (t(2916) = -0.21, ns), or P8 (t(2916) = -0.27, ns). fMRI showed no change in activation for the hand but an increase in activation post-bed rest for the leg. On an individual basis, a more heterogeneous response was found which showed a potential association with performance on FMT. Results of this research include a better understanding of the cortical plasticity associated with leg disuse and may lead to applications in patient and astronaut rehabilitation.