Background: Caring child with Down Syndrome (DS) requires special challenges, and mothers can go through a period of difficulty adapting. So, coping strategies with positive attitudes are considered effective in improving quality of life for mothers and their children. Aim: The study aimed to evaluate the effectiveness of coping strategies intervention on quality of life for mothers having children with Down Syndrome. Method: A quasi-experimental research design (one group pre/posttest) was used. Setting: This study was conducted at the Genes Clinics of DS in the Specialized Clinics of Pediatric Hospital affiliated to Ain Shams University. Sample: A purposive sample consisted of (75) mothers and their children with down syndrome recruited from the above-mentioned setting. Tools: Five tools were used pre /post intervention to collect data; A structured interviewing questionnaire to assess mothers' knowledge related to DS; Self-reliance assessment to assess level of independence of DS children regarding daily living activities as reported by their mothers; Needs' scale to assess cognitive, economical, psychological, social, and physical needs experienced by the mothers; Coping patterns scale to assess the mothers' coping patterns toward their DS children, and Family quality of life scale to assess health related Quality of Life (QoL) for mothers of children with down syndrome. Results: There was a highly statistically significant improvement was observed between the studied mothers' knowledge, QoL, needs, and coping patterns pre and post intervention program, where p < 0.001, also there was a positive correlation between total self-reliance of the studied children and total mothers' needs, quality of life and coping at pre and post intervention program (p=< 0.001). Conclusion: Implementation of coping strategies intervention had a positive effect on the improvement of mothers' knowledge, level of needs, coping patterns and quality of life. Recommendations: Conducting frequent educational program focused on encouraging mothers to cope effectively with their children with DS.