Levetiracetam (LEV) is an antiepileptic drug (AED) that has been shown to mainly enhance synaptic depression and modulate certain voltage and ligand-gated channels, after it gains entry into neurons through endocytosis. Since synaptic terminals and distal axons are the first compartments exposed to LEV, we utilized a crayfish motor axon preparation to investigate whether LEV modulates axonal excitability. Two electrode current clamp from the inhibitor axon of the crayfish opener showed that LEV reduced action potential amplitude (APamp) and enhanced synaptic depression, although these events did not occur at the same time, the latter occurred later than the reduction in APamp. Further examinations of these effects and comparison of antidromic and orthodromic conducting action potentials in LEV suggests that this drug preferentially reduces excitability of the proximal axon despite the expectation that it enters the axon at terminals and reaches distal branches first. Results presented here demonstrate that LEV modulates axonal excitability, which may also contribute to its antiepileptic effects.