Down’s syndrome (DS), or Trisomy 21, represents the most common chromosomal abnormality in live births, characterized by an extra chromosome 21. Children affected by Down’s syndrome are more susceptible to the development of obesity and of becoming overweight compared with other children. Furthermore, they seem to present a more unfavorable lipid profile than the non-DS obese pediatric population. Diet and physical activity are closely related to the development of overweight and obesity, and they can be assessed using questionnaires such as the Mediterranean Diet Quality Index in children and adolescents (KIDMED) and the Godin–Shephard Leisure-Time Physical Activity Questionnaire. This review aims to undertake a comprehensive analysis of the intricate interplay between diet and physical activity in children affected by Down’s syndrome. Specifically, it seeks to deepen understanding regarding the question of how diet and exercise can influence and prevent the development of overweight and obesity in that special pediatric population.