Transcranial magnetic stimulation (TMS) has been employed in multiple sclerosis (MS) to assess the integrity of the corticospinal tract and the corpus callosum and to explore some physiological properties of the motor cortex. Specific alterations of TMS measures have been strongly associated to different pathophysiological mechanisms, particularly to demyelination and neuronal loss. Moreover, TMS has contributed to investigate the neurophysiological basis of MS symptoms, particularly those not completely explained by conventional structural damage, such as fatigue. However, variability existing between studies suggests that alternative mechanisms should be involved. Knowledge of MS pathophysiology has been enriched by experimental studies in animal models (i.e., experimental autoimmune encephalomyelitis) demonstrating that inflammation alters synaptic transmission, promoting hyperexcitability and neuronal damage. Accordingly, TMS studies have demonstrated an imbalance between cortical excitation and inhibition in MS. In particular, cerebrospinal fluid concentrations of different proinflammatory and anti-inflammatory molecules have been associated to corticospinal hyperexcitability, highlighting that inflammatory synaptopathy may represent a key pathophysiological mechanism in MS. In this perspective article, we discuss whether corticospinal excitability alterations assessed with TMS in MS patients could be useful to explain the pathophysiological correlates and their relationships with specific MS clinical characteristics and symptoms. Furthermore, we discuss evidence indicating that, in MS patients, inflammatory synaptopathy could be present since the early phases, could specifically characterize relapses, and could progressively increase during the disease course.