This prospective, observational study examined the effects of change in the symptoms of fatigue and depression on physical activity over time in persons with relapsing-remitting multiple sclerosis (RRMS). Adults with a confirmed diagnosis of RRMS completed a battery of questionnaires at baseline (n = 269) and six-month follow-up (n = 263). The data were analyzed using linear panel analysis and covariance modeling in Mplus 3.0. The panel model fit the data (χ(2) = 24.00, df = 15, p = 0.07, SRMR = 0.04, CFI = 0.98) and demonstrated that changes in both fatigue (path coefficient = -0.09) and depressive symptoms (path coefficient = -0.12) were significantly associated with residual change in physical activity. Such findings support the importance of fatigue and depression for predicting longitudinal changes in physical activity in adults with RRMS.