The aim of the Bright Start study was to develop and test the effectiveness of a school environment intervention, supplemented with family involvement, to reduce excessive weight gain by increasing physical activity and healthy eating practices among kindergarten and first-grade American Indian children. Bright Start was a group-randomized, school-based trial involving 454 children attending 14 schools on the Pine Ridge Reservation in South Dakota. Children were followed from the beginning of their kindergarten year through the end of first grade. Main outcome variables were mean BMI, mean percent body fat, and prevalence of overweight/obese children. The goals of the intervention were to: increase physical activity at school to at least 60 min/day; modify school meals and snacks; and involve families in making behavioral and environmental changes at home. At baseline, 32% of boys and 25% of girls were overweight/obese. Although the intervention was not associated with statistically significant change in mean levels of BMI, BMI-Z, skinfolds or percentage body fat, the intervention was associated with a statistically significant net decrease of 10% in the prevalence of overweight. Intervention children experienced a 13.4% incidence of overweight, whereas the control children experienced a corresponding incidence of 24.8%; a difference of −11.4% (P = 0.033). The intervention significantly reduced parent-reported mean child intakes of sugar-sweetened beverages, whole milk, and chocolate milk. Changes in duration of school physical activity were not significant. Because obesity is the most daunting health challenge facing American Indian children today, more intervention research is needed to identify effective approaches.