Introduction The COVID-19 pandemic caused major changes in the lifestyle and in the access to health services worldwide. Progressive multiple sclerosis (pMS) patients are a vulnerable population at high risk of disability worsening. Objective and Methods The objective of this study was to assess the health outcomes of COVID-19 lockdown in a cohort of 225 pMS patients. Results Worsening of neurological disability (19.7%) and fatigue (32.4%), depression (30.4%), and weight increase (28.3%) were observed in pMS patients during lockdown, along with discontinuation of regular physical exercise (47.1%) and of physical therapy (59.3%). Conclusion These results highlight the adverse impact, on pMS patients, of the public health measures implemented for the containment of the pandemic.