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Purpose: Physical activity provides a wide range of benefits. Several studies conducted in various countries have examined factors influencing participation in physical activities in children with Down syndrome. This study aimed to explore factors affecting participation in physical activities in Saudi children with DS, from their mothers' perspectives. Materials and methods: In-depth interviews were conducted with 36 mothers of children with Down syndrome to explore facilitators of and barriers to their children's participation in physical activities. All audio recordings were transcribed, validated, reviewed by the authors independently, and organized into themes. Results: Transcript analysis resulted in four facilitators (mother's support and siblings' involvement, involvement of peers, type of physical activity experience, and child's physical ability, behavioral, and psychological status), and six barriers (conditions associated with Down syndrome, family responsibility, social barriers, environmental constraints, electronic devices, and mother's personal psychological barriers). Conclusions: The results regarding perceived barriers indicated a need to develop and implement programs involving family consultation. Environmental modifications should be made to accommodate the needs of children with Down syndrome. A well-organized partnership should be established and activated between private investors and the Ministries of Education, Social Affairs, and Health, to support the promotion of physical activity.