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Fat mass and obesity-associated (FTO) gene influences obesity but studies have shown that environmental/lifestyle variables like physical activity (PA), time spent sitting (TSS), and energy intake might mediate the effect. However, this is poorly understood in Nigeria due to scarce studies. We demystified association and interaction between FTO rs9939609, obesity, PA, TSS, and energy intake in Nigeria. FTO gene variant was genotyped by restriction fragment length polymorphism and gene sequencing analysis in 103 people with obesity and 98 controls. Anthropometrics and environmental variables were measured using standard procedures. Significant associations were found between FTO rs9939609 with obesity and environmental/lifestyle variables before and after adjusting for age. Carriers of allele A have significantly higher odds of being overweight/obese using BMI [0.191 (0.102–0.361), p < 0.001] but this was attenuated by PA (p[interaction] = 0.029); odds of being overweight reduced from 0.625 (0.181–2.159) to 0.082 (0.009–0.736) for low and high PA, respectively. Mediation analysis of total indirect effect also confirmed this by showing a simultaneous mediating role of total PA, energy intake, and TSS in the relationship between FTO and BMI (unstandardized-coefficient = 1.68; 95% CI: 1.26–2.22). This study shows a relationship between FTO and obesity phenotype and environmental/lifestyle factors might be an important modulator/mediator in the association.