Long-term psychological stress is associated with BMI increases in children as they transition to adulthood, whereas long-term maintenance of physical activity can slow excess weight gain. We hypothesized that in addition to these main effects, long-term physical activity mitigates the relationship between long-term stress and BMI increase.The NHLBI Growth and Health Study enrolled 2,379 10-year-old Black and White girls, following them annually for 10 measurement points. Growth curve modeling captured the dynamics of BMI, measured yearly, and stress and physical activity, measured at varying years.At average levels of activity and stress, with all covariates remaining fixed, average BMI at baseline was 19.74 (SE = 0.38) and increased 0.64 BMI (SE = 0.01, p < .001) units every year. However, this increase in BMI significantly varied as a function of cumulative stress and physical activity. Slower BMI gain occurred in those girls who were less stressed and more active (0.62 BMI units/year, SE = .02, p < .001), whereas the most rapid and largest growth occurred in girls who were more stressed and less active (0.92 BMI units/year, SE = .02, p < .001). Racial identification did not alter these effects.As hypothesized, in girls who maintained long-term activity, BMI growth was mitigated, even when reporting high long-term stress, compared with less physically active girls. This study adds to a converging literature in which physical activity, a modifiable prevention target, functions to potentially limit the damaging health effects of long-term psychological stress.