BackgroundDown syndrome (DS) is the most frequent genetic mental disability. Individuals with DS experience a variety of physical, motor, and functional challenges throughout the lifespan. However, the inter-relatedness between these domains is relatively unexplored in children with DS. This study aimed to determine which physical and motor characteristics contribute to functional performance in children and adolescents with DS. It also investigated the relationship between physical, motor, and functional domains.Material/MethodsWe enrolled 44 children and adolescents with DS, ages 3–18 years, in this cross-sectional study. The participants were assessed for functional skills (PEDI-CAT), gross motor skills (GMFM-88), balance (PBS), fine motor skills (Nine-hole peg test), grip strength (hand-held Jamar dynamometer), and body mass index (BMI). Descriptive statistics, Pearson’s correlation, and stepwise linear regression were employed for statistical analysis.ResultsFine motor skills and grip strength were found to be significant predictors of functional performance. All measures, except BMI, were significantly correlated with each other. The participants scored below standard values in all 4 domains of PEDI-CAT, with the social/cognitive skills being most impaired, while mobility proficiency was found to be participants’ strongest asset.ConclusionsThis study demonstrated fine motor skills and grip strength to be predictors of functional performance in children and adolescents with DS. It also showed a high level of inter-relatedness between the variables of physical, motor, and functional domains in this population.