Evolution of the direct connection from primary motor cortex to motoneurons in the spinal cord parallels acquisition of hand dexterity and lateralization of hand preference. Recent studies indicated that the phylogenetically older pathway consisting of multi-synaptic connections from primary motor cortex to spinal motoneurons also participate in controlling dexterous hand movement. However, it remains unknown how the two corticospinal pathways work in concert to control unilateral hand movement with lateralized preference. Using corticospinal functional magnetic resonance imaging, we discovered the asymmetric organization of the two corticospinal networks that modelled monosynaptic or polysynaptic control from primary motor cortices over spinal motoneurons. Moreover, the degree of the involvement of the two corticospinal networks paralleled the lateralization of hand preference. The present results pointed to the functionally lateralized motor nervous system that underlies the behavioural asymmetry of handedness, a uniquely human trait which could have phylogenetically differentiated humans from other primates.