Background and purpose Loss of long‐term potentiation (LTP) expression has been associated with a worse disease course in relapsing–remitting multiple sclerosis (RR‐MS) and represents a pathophysiological hallmark of progressive multiple sclerosis (PMS). Exercise and physical rehabilitation are the most prominent therapeutic approaches to promote synaptic plasticity. We aimed to explore whether physical exercise is able to improve the expression of LTP‐like plasticity in patients with multiple sclerosis (MS). Methods In 46 newly diagnosed RR‐MS patients, we explored the impact of preventive exercise on LTP‐like plasticity as assessed by intermittent theta‐burst stimulation. Patients were divided into sedentary or active, based on physical activity performed during the 6 months prior to diagnosis. Furthermore, in 18 patients with PMS, we evaluated the impact of an 8‐week inpatient neurorehabilitation program on clinical scores and LTP‐like plasticity explored using paired associative stimulation (PAS). Synaptic plasticity expression was compared in patients and healthy subjects. Results Reduced LTP expression was found in RR‐MS patients compared with controls. Exercising RR‐MS patients showed a greater amount of LTP expression compared with sedentary patients. In PMS patients, LTP expression was reduced compared with controls and increased after 8 weeks of rehabilitation. In this group of patients, LTP magnitude at baseline predicted the improvement in hand dexterity. Conclusions Both preventive exercise and physical rehabilitation may enhance the expression of LTP‐like synaptic plasticity in MS, with potential beneficial effects on disability accumulation.