Fatigue represents a hallmark symptom in Multiple Sclerosis (MS), but its diagnosis and clinical evaluation is difficult because it is described as a subjective feeling of exhausted physical and mental sensation. Studies have also shown that approaches based on assisted therapies and robotics, as well as the use of vibration, which are used to improve sensory integration, reduce fatigue. The primary outcome in this study is to evaluate the effects of the application of focal vibrations on the reduction in fatigue, muscle strength, and endurance in MS patients with moderate disability. The secondary outcome is to assess the effects on quality of life, cognitive status, and mood. We enrolled 40 MS patients. The study was designed as a parallel randomized controlled trial: 20 patients were assigned to the experimental group (EG), who received vibration training, and 20 to the control group (CG), who received traditional physical exercise. We found significant differences in the EG in fatigue, motor, and cognitive outcome and improvement of some aspects of quality of life (QoL). There are correlations between perceived multidimensional fatigue and cadence, step length, and health quality of life composite. Our study demonstrated the potential effectiveness of vibration training in balance, walking endurance, and reduction in the risk of falls in patients with Multiple Sclerosis. In addition, we added evidence about fatigue, non-motor outcomes, in particular promoting mental and physical QoL and individual life satisfaction. The name of the registry is clinicaltrial.gov; the number of registration id NCT05783999; and the date of registration is 14 March 2023.