BACKGROUND: Multiple sclerosis (MS) has a huge impact on patients and affects their ability to participate in meaningful activities. OBJECTIVE: To identify motor and non-motor factors that are associated with the participation level in instrumental activities of daily living (IADL), leisure, social and religious activities in people with MS. METHOD: This is a cross-sectional study conducted on 110 individuals with MS. The used outcome measures are: Arabic version of the Activity Card Sort, Berg Balance Scale, Modified Fatigue Impact Scale, Nine Hole Peg Test, 6-Minute Walk Test, Brief International Cognitive Assessment for Multiple Sclerosis, Stroop test and Hospital Anxiety and Depression Scale. RESULTS: Hand function, balance, gender and cognitive status can predict the participation in IADL (R2 = 0.425, P < 0.0001); depression, age, and cognitive status can predict the participation in leisure activities (R2 = 0.372, P < 0.0001), and fatigue, balance and cognitive status can predict social activities participation (R2 = 0.492, P < 0.000). CONCLUSION: Balance, cognition and fatigue affect the level of participation in instrumental activities of daily living, leisure, and religious and social activities.