Individuals with multiple sclerosis (MS) are substantially less physically active than nondiseased populations. Unique aspects of MS, such as symptomology, may partially account for this inactivity. Cross-sectional research has shown that elevated symptomology is associated with lower levels of physical activity participation in individuals with MS. The primary purpose of this study was to examine the role of naturally-occurring change in MS-related symptoms as a predictor of change in physical activity behavior across 6 months among individuals with MS. The hypothesized relationships between symptoms and physical across six months were based on the Theory of Unpleasant Symptoms. A panel model study design within a covariance modeling framework was used. At Baseline (N = 292) and 6 Months (N = 277) participants completed the MS-Related Symptom Scale, Symptom Inventory, Multiple Sclerosis Impact Scale-29, Godin Leisure Time Exercise Questionnaire and wore an accelerometer for 7 days. The three symptom questionnaires served as indicators for the symptom (i.e., overall symptom burden) latent variable and the two measures of physical activity were indicators for the physical activity latent variable. The panel model provided a good fit for the data (χ² = 21.81, df = 24, p = 0.59, RMSEA = 0.00, 90% CI = 0.00–0.04, CFI = 1.00). MS-related symptoms at Baseline were predictive of symptoms at 6 Months (γ = 0.90), but they were not predictive of physical activity at 6 Months (γ = 0.17). Physical activity at Baseline was predictive of physical activity at 6 Months (γ = .92), but it was not predictive of MS-related symptoms at 6 months (γ = -0.04). There was a moderate inverse relationship between MS-related symptoms and physical activity behavior at Baseline (γ = -0.46), however there was not a significant relationship between changes in MS-related symptoms and changes in physical activity across the study β = -0.21). The results of this study provide further support of the cross-sectional relationship between symptoms and physical activity and are partially consistent with the hypothesized relationships based on the Theory of Unpleasant Symptoms.