The mechanisms driving cortical plasticity in response to brain stimulation are still incompletely understood. We here explored whether neural activity and connectivity in the motor system relate to the magnitude of cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS). Twelve right-handed volunteers underwent functional magnetic resonance imaging during rest and while performing a simple hand motor task. Resting-state functional connectivity, task-induced activation, and task-related effective connectivity were assessed for a network of key motor areas. We then investigated the effects of intermittent theta-burst stimulation (iTBS) on motor-evoked potentials (MEP) for up to 25 min after stimulation over left primary motor cortex (M1) or parieto-occipital vertex (for control). ITBS-induced increases in MEP amplitudes correlated negatively with movement-related fMRI activity in left M1. Control iTBS had no effect on M1 excitability. Subjects with better response to M1-iTBS featured stronger preinterventional effective connectivity between left premotor areas and left M1. In contrast, resting-state connectivity did not predict iTBS aftereffects. Plasticity-related changes in M1 following brain stimulation seem to depend not only on local factors but also on interconnected brain regions. Predominantly activity-dependent properties of the cortical motor system are indicative of excitability changes following induction of cortical plasticity with rTMS.