Focal extracorporeal shock wave therapy (fESWT) is a physical therapy vastly studied and used for various musculoskeletal disorders. However, the effect of fESWT on central nervous system is still to be determined. To elucidate spinal and supra-spinal mechanisms of fESWT in healthy subjects, in order to widen the spectrum of its clinical applications. In this quasi-experimental, unblinded, proof-of-concept clinical study, 10 voluntary healthy subjects underwent fESWT and were assessed immediately before (T0), immediately after (T1) and seven days after (T2) the intervention. As neurophysiological outcomes, motor evoked potentials (resting motor threshold, maximal motor evoked potential and maximal compound muscle action potential ratio, cortical silent period, total conduction motor time, direct and indirect central motor conduction time), F-waves (minimal and mean latency, persistence and temporal dispersion) and H-reflex (threshold, amplitude, maximal H reflex and maximal compound muscle action potential ratio, latency) were considered. Resting motor threshold and F-waves temporal dispersion significantly decreased, respectively, from T1 and T2 and from T0 and T2 (for both, p < 0.05). H-reflex threshold increase between T0 and T1. Analysis disclosed a strong negative correlation between Δ3 cortical silent period (i.e., T2 -T1 recordings) and Δ1 Hr threshold (i.e., T1 -T0 recordings) (r = -0.66, p < 0.05), and a positive strong relationship between Δ3 cortical silent period and Δ3 Hr threshold (r = 0.63, p < 0.05). fESWT modulates corticospinal tract excitability in healthy volunteers, possibly inducing an early inhibition followed by a later facilitation after one week.