Smoking rates among adolescents is still prevalent in the United States and the majority of adult smokers began smoking before age 18. The steep decline in youth smoking observed over since the late 1990s has stagnated since the mid-2000s. Many risk factors for smoking have been identified at the individual level, in intermediate social environment, as well as the larger contextual social environment, yet not much is known about the cross-level interaction between individual factors and the macro environment and tobacco use. The purpose of this gene-environment study was to examine the moderating effects of state-level anti-tobacco efforts on the genetic risk factors associated with tobacco use. This secondary analysis study relied on the National Longitudinal Adolescent Health Survey dataset that had genotype information for 10 genetic polymorphisms for the sibling subset (n = 2,574). Hierarchical linear modeling identified 10 significant gene-environment interactions for three polymorphisms, CHRNA6 rs230497, CHRNB3 rs4950, and CYP2A6, directly associated with tobacco use and addiction, and four state-level policies, full-time equivalent staff (FTEs) dedicated to anti-tobacco efforts per 100,000 residents, excise tax, and tobacco control funding for the general population and for youth. Nine out of the 10 interactions enhanced the genetic influence on smoking behaviors; increase in excise tax, number of FTEs, and tobacco funding increased number of days smoking and cigarettes per day and decreased the likelihood of being a never smoker or having a quit attempt in youth with high-risk genetic profiles.