The aim of this study was to investigate the feasibility of automatically assessing the 2-Minute Walk Distance (2MWD) for monitoring people with multiple sclerosis (pwMS). For 154 pwMS, MS-related clinical outcomes as well as the 2MWDs as evaluated by clinicians and derived from accelerometer data were collected from a total of 323 periodic clinical visits. Accelerometer data from a wearable device during 100 home-based 2MWD assessments were also acquired. The error in estimating the 2MWD was validated for walk tests performed at hospital, and then the correlation (r) between clinical outcomes and home-based 2MWD assessments was evaluated. Robust performance in estimating the 2MWD from the wearable device was obtained, yielding an error of less than 10% in about two-thirds of clinical visits. Correlation analysis showed that there is a strong association between the actual and the estimated 2MWD obtained either at hospital (r = 0.71) or at home (r = 0.58). Furthermore, the estimated 2MWD exhibits moderate-to-strong correlation with various MS-related clinical outcomes, including disability and fatigue severity scores. Automatic assessment of the 2MWD in pwMS is feasible with the usage of a consumer-friendly wearable device in clinical and non-clinical settings. Wearable devices can also enhance the assessment of MS-related clinical outcomes.