Background: Physical activity is one way that persons with multiple sclerosis (MS) (PwMS) can manage disease symptoms and progression. Unfortunately, PwMS do experience symptoms of poorer mental and cognitive health, and tend to be less physically active than the general population. This underscores the need for an increased understanding of the factors associated with exercise in PwMS. Objectives: To examine the association between mental and cognitive health and physical activity in PwMS. Methods: The study included 640 PwMS in the iConquerMS cohort who completed the demographic, physical activity, and Neuro-QoL surveys within a 30 day period. The outcome was a sum of answers to the questions considering a 7-day period (a week), how many times on average do you do the following kinds of activity for more than 15 minutes during your free time? for strenuous, moderate, and mild physical activity. The outcome was examined as both a count of sessions, via multivariable zero-inflated negative binomial regression, and as a binary outcome of meeting a recommended 4 weekly sessions, via multivariable logistic regression. Patient-reported outcomes (PROs) of depression, cognitive function, positive affect, and leg function were measured via Neuro-QoL. Age, race, sex, MS subtype, season of survey, region, and body mass index (BMI) were covariates. Results: The study sample was 91% non-Hispanic white, 83% female, 65% relapsing remitting (RR) MS, 16.1% secondary progressive (SP) MS, and 5% clinically/radiologically isolated syndrome (CIS/RIS). The mean age was 52 years. For both analyses, BMI category and disability were inversely associated with engagement in physical activity, while depression and cognitive function were mixed in significance. Positive affect was dropped due to collinearity. A one-point increase in leg function score, indicating less disability, was associated with 16% lower odds of engaging in exercise (95% CI = 0.80-0.88), but among those who did engage, a one-point increase was associated with 2% more weekly sessions (95% CI = 1.01-1.03). Increased symptoms of depression were correlated with lowered odds of exercise engagement and meeting recommendations, regardless of disability stratum. Conclusions: These results suggest exercise to be associated with cognitive and mental PROs among PwMS, especially pertaining to disability and depression, implying that these factors should be considered in the design of physical activity interventions among PwMS.