Coincident hand and foot movements are more reliably performed in the same direction than in opposite directions. Using transcranial magnetic stimulation (TMS) to assess motor cortex function, we examined the physiological basis of these movements across three novel experiments. Experiment 1 demonstrated that upper limb corticomotor excitability changed in a way that facilitated isodirectional movements of the hand and foot, during phasic and isometric muscle activation conditions. Experiment 2 demonstrated that motor cortex inhibition was modified with active, but not passive, foot movement in a manner that facilitated hand movement in the direction of foot movement. Together, these findings demonstrate that the coupling between motor representations within motor cortex is activity dependent. Because there are no known connections between hand and foot areas within primary motor cortex, experiment 3 used a dual-coil paired-pulse TMS protocol to examine functional connectivity between secondary and primary motor areas during active ankle dorsiflexion and plantarflexion. Dorsal premotor cortex (PMd) and supplementary motor area (SMA) conditioning, but not ventral premotor cortex (PMv) conditioning, produced distinct phases of task-dependent modulation of excitability of forearm representations within primary motor cortex (M1). Networks involving PMd-M1 facilitate isodirectional movements of hand and foot, whereas networks involving SMA-M1 facilitate corticomotor pathways nonspecifically, which may help to stabilize posture during interlimb coordination. These results may have implications for targeted neurorehabilitation after stroke.