Skillful goal-directed manual actions such as grasping and manipulating objects are supported by a large sensorimotor network. Within this network, the ventral premotor cortex (PMv) transforms visual information about objects into motor commands that are conveyed to the primary motor cortex (M1), allowing fine control of finger movements. However, it is unknown whether transcranial magnetic stimulation (TMS) of this PMv-to-M1 hierarchical pathway improves action performance. To fill in this gap, here, we used cortico-cortical paired associative stimulation (ccPAS) with the aim of manipulating synaptic efficacy in the human PMv-to-M1 pathway. We found that repeatedly pairing TMS of pre-and post-synaptic nodes of the PMv-to-M1 pathway (i.e., PMv-to-M1 ccPAS) increased motor excitability and enhanced performance on the 9-Hole Peg Test (9-HPT), which taps into PMv-M1 functioning. These effects were specific to the ccPAS protocol consistent with the direction of the PMv-to-M1 hierarchy, as no effects were observed when reversing the order of the paired TMS pulses (i.e., following a M1-to-PMv ccPAS) or when administering sham ccPAS. Additionally, the effect of PMv-to-M1 ccPAS appeared functionally specific, as no behavioral enhancement was observed in a visuomotor control task. We therefore provide novel causal evidence that the PMv-to-M1 pathway, which is instrumental to object-oriented hand actions, is sensitive to TMS manipulations of associative plasticity. Our study highlights the causal role of the PMv-to-M1 pathway in controlling skillful object-oriented hand actions and suggests that ccPAS might be a useful tool for investigating the functional relevance of directional connectivity in humans. These findings may have implications for designing novel therapeutic strategies based on the manipulation of associative plasticity in cortico-cortical networks.