While the impact of physical disabilities on daily activities is well documented, less is known about the influence of nonmotor symptoms on activities and participation. This study aims to fill this gap by examining how nonmotor symptoms affect activities and participation outcomes in wheelchair users with multiple sclerosis (MS). Data from 89 wheelchair users with MS collected through a nationwide survey were analyzed. Participants completed the Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function, PROMIS depression, PROMIS pain interference, Fatigue Severity Scale, and measures of self-efficacy and participation. Hierarchical multivariable linear regression was used to assess the impact of nonmotor symptoms on four self-efficacy and participation outcomes beyond physical function. As expected, physical function was a significant predictor of all outcomes: self-efficacy for managing daily activities (β = 0.59, P