Down syndrome (DS) is a chromosomal condition that is characterized by multiple pathological phenotypes. Oxidative stress caused by DS in individuals leads to DS phenotypes, which include various morphological abnormalities and externalizing disorders. Oxidative stress is an imbalance between the production of free radicals and reactive metabolites and the antioxidant defenses. Considering the physical and behavioral problems of adolescents with DS, the family is the first source of support for these adolescents. So one of the methods that can help adolescents with DS is family-based intervention. This study aimed to investigate the effects of family-based interventions on oxidative stress and social skills of adolescents with DS. The design of the research was quasi-experimental and pre-test/post-test with a control group. The study sample was 24 adolescents with DS in Rasht City, Guilan Province, Iran, in 2023, who were selected by the convenience sampling method. To collect data, blood laboratory evaluation and strengths and difficulties questionnaire (teacher form) were used before and after the training. The experimental group received behavioral management group training for 10 sessions, and the control group did not receive any training. Data were analyzed using univariate and multivariate analysis of covariance. The results showed that family-based interventions improved oxidative stress and increased social skills of adolescents with DS (p < 0.001). According to these results, family-based interventions can have important implications for social adaptation and the prevention of physical problems in individuals with DS.