Unilateral lengthening contractions provide a greater stimulus for neuromuscular adaptation than shortening contractions in the active and non-active contralateral homologous muscle, although little is known of the potential mechanism. Here we examined the possibility that corticospinal and spinal excitability vary in a contraction-specific manner in the relaxed right flexor carpi radialis (FCR) when humans perform unilateral lengthening and shortening contractions of the left wrist flexors at the same absolute force. Corticospinal excitability in the relaxed right FCR increased more during lengthening than shortening at 80 and 100% of maximum voluntary contraction (MVC). Short-interval intracortical inhibition (SICI) diminished during shortening contractions and it became nearly abolished during lengthening. Intracortical facilitation (ICF) lessened during shortening but increased during lengthening. Interhemispheric inhibition (IHI) to the "non-active" motor cortex diminished during shortening and became nearly abolished during lengthening at 90% MVC. The amplitude of the H-reflex in the relaxed right FCR decreased during and remained depressed for 20 s after lengthening and shortening of the left wrist flexors. We discuss the possibility that instead of the increased afferent input, differences in the descending motor command and activation of brain areas that link function of the motor cortices during muscle lengthening vs. shortening may cause the contraction-specific modulation of ipsilateral motor cortical output. In conclusion, ipsilateral M1 responses to TMS are contraction-specific; unilateral lengthening and shortening contractions reduced contralateral spinal excitability but uniquely modulated ipsilateral corticospinal excitability and the networks involved in intracortical and interhemispheric connections, which may have clinical implications.