Introduction <p>Thalamic atrophy is a highly common and disabling consequence of multiple sclerosis (MS) that occurs early in the disease process, progressively worsens over time, and negatively impacts functional and quality of life outcomes in patients. Long-term aerobic walking exercise training (ET), in particular, represents a promising approach for mitigating MS-related thalamic atrophy and its downstream consequences in persons with MS.</p> Methods <p>The present early-stage trial examined the feasibility of two different doses of a 12-month remotely delivered and supported aerobic walking ET program on thalamic volume and its downstream outcomes of cognitive processing speed, walking performance, and quality of life in 25 fully-ambulatory persons with MS who were pre-screened for slowed cognitive processing speed.</p> Results <p>The 12-month trial was feasible in terms of process, resource, and management metrics, and the 12-month exercise prescriptions were both safe and associated with high adherence rates. However, the higher-dose walking ET prescription was too difficult in terms of duration and intensity. Regarding scientific feasibility, with the data pooled across conditions, 12-months of remotely delivered and supported aerobic walking ET was associated with preservation of thalamic volume (<i>d</i> = 1.01), along with benefits on cognitive processing speed (<i>d</i> = 0.41), walking endurance (<i>d</i> = 0.33), and aerobic fitness overall (<i>d</i> = 0.48).</p> Conclusions <p>Collectively, the present feasibility data support the design and testing of a subsequent randomized controlled trial of 12-months of remotely delivered and supported aerobic walking ET on thalamic volume/atrophy and its downstream consequences in persons with MS.</p>