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Background Child and adolescent overweight and obesity rates are increasing rapidly, notably in middle-income countries (MICs). Effective policy adoption has been limited in low-income and middle-income countries. To respond, investment cases were developed in Mexico, Peru, and China to understand the health and economic returns on investment in childhood and adolescent overweight and obesity interventions. Methods The investment case model applied a societal perspective to predict the health and economic impact of childhood and adolescent overweight and obesity in a cohort aged 0–19 years, beginning in 2025. Impacts include health-care expenditures, years of life lost, reduced wages, and productivity. Unit cost data from the literature was used to develop a status quo scenario over the model cohort's average expected lifetime period (2025–90 in Mexico; 2025–92 in China and Peru) and was compared with an intervention scenario to estimate cost savings and calculate return on investment (ROI). Effective interventions were identified from the literature and selected to reflect country-specific prioritization after stakeholder discussions. Priority interventions range from fiscal policies, social marketing, breastfeeding promotion, school-based policies, and nutritional counselling. Findings Total predicted lifetime health and economic impacts of child and adolescent overweight and obesity in the three countries ranged from US$1·8 trillion in Mexico, $211 billion in Peru, and $33 trillion in China. Implementing a set of priority interventions in each country could reduce lifetime costs by $124 billion (Mexico), $14 billion (Peru), and $2 trillion (China). Implementing a unique package of interventions for each country resulted in a predicted lifetime ROI of $515 per $1 invested in Mexico, $164 per $1 in Peru, and $75 per $1 in China. Fiscal policies were very cost-effective and had positive ROIs in all three countries for 30-year, 50-year, and lifetime time horizons until 2090 (Mexico) or 2092 (China and Peru). Although school interventions had a positive ROI in all countries across a lifetime horizon, relatively they yielded considerably lower ROIs than other interventions evaluated. Interpretation Lifetime health and economic impacts of child and adolescent overweight and obesity across the three MICs are high and will undermine countries’ ability to meet sustainable development goals. Investing in nationally relevant cost-effective interventions could reduce lifetime costs. Funding UNICEF, partly supported by a grant from Novo Nordisk. Contributors AJM supervised and contributed to conceptualisation. CLM contributed to the formal analysis. Both authors wrote the original draft and reviewed and edited it.