Probing the brain structure-function relationship is at the heart of modern neuroscientific explorations, enabled by recent advances in brain mapping techniques. This study aimed to explore the anatomical blueprint of corticospinal excitability and shed light on the structure-function relationship within the human motor system. Using diffusion magnetic resonance imaging tractography, based on the spherical deconvolution approach, and transcranial magnetic stimulation (TMS), we show that anatomical inter-individual variability of the corticospinal tract (CST) modulates the corticospinal excitability and conductivity. Our findings show for the first time the relationship between increased corticospinal excitability and conductivity in individuals with a bigger CST (i.e., number of streamlines), as well as increased corticospinal microstructural organization (i.e., fractional anisotropy). These findings can have important implications for the understanding of the neuroanatomical basis of TMS as well as the study of the human motor system in both health and disease.