Phenotypic plasticity is known to enhance population persistence, facilitate adaptive evolution and initiate novel phenotypes in novel environments. How plasticity can contribute or hinder adaptation to different environments hinges on its genetic architecture. Even though plasticity in many traits is genetically controlled, whether and how plasticity's genetic architecture might change in novel environments is still unclear. Because much of gene expression can be environmentally influenced, each environment may trigger different sets of genes that influence a trait. Using a quantitative trait loci (QTL) approach, we investigated the genetic basis of plasticity in a classic functional trait, alcohol dehydrogenase (ADH) activity in D. melanogaster, across both historical and novel alcohol environments. Previous research in D. melanogaster has also demonstrated that ADH activity is plastic in response to alcohol concentration in substrates used by both adult flies and larvae. We found that across all environments tested, ADH activity was largely influenced by a single QTL encompassing the Adh-coding gene and its known regulatory locus, delta-1. After controlling for the allelic variation of the Adh and delta-1 loci, we found additional but different minor QTLs in the 0 and 14% alcohol environments. In contrast, we discovered no major QTL for plasticity itself, including the Adh locus, regardless of the environmental gradients. This suggests that plasticity in ADH activity is likely influenced by many loci with small effects, and that the Adh locus is not environmentally sensitive to dietary alcohol.