Not much is known about the role of physical activity (PA), obesity related variables, and trace elements as potential risk factors affecting neurotransmitters in schoolchildren with depression. Our objective was to investigate the effect of physical activity (PA) on depressive symptoms in children and adolescents. Also, we aimed to study the association of demographic variables, serum levels of Copper (Cu), Zinc (Zn), serotonin, and salivary cortisol with depression in this population. One hundred and fifty school children (90 boys and 60 girls) aged 7-18years were recruited for this study. All participants were evaluated for depression using CDI-score analysis. Their physical activity levels were checked using pre-validated questionnaires. The serum levels of Copper (Cu), Zinc (Zn), cortisol, and serotonin were estimated using atomic absorption, and immunoassay techniques. About 48.7% of the study population had depressive symptoms (CDI-score; ≥13), and were classified into mild, moderate, and severe categories. Older children, especially girls, had higher levels of depression. Participants with moderate and severe depression had significantly lower physical activity, serotonin, and zinc levels, Zn/Cu ratios, and significantly higher copper and cortisol levels. Physically active boys showed significantly lower depressive CDI-scores and improvement in cortisol, serotonin, Cu, and Zn concentrations compared to girls of sedentary life style. CDI- scores correlated positively with BMI, cortisol and Cu, and negatively with PA, serotonin and Zn concentrations. BMI, cortisol, serotonin, Cu and Zn, could explain about 59.3-79% of the depressive symptoms among schoolchildren, according to stepwise regression analysis. This was especially true in especially older girls. PA and an adequate balance in Zn and Cu levels, plays a positive role in improving CDI-depressive score, BMI, serotonin and cortisol levels among schoolchildren.