Ethylene response factors 2 (ERF2) are essential for plant growth, fruit ripening, metabolism, and resistance to stress. In this study, the levels of expression of the genes for MdERF2 implicated in the biosynthesis of fruit cuticular wax, composition of wax, and ultrastructure in apple (Malus domestica) were studied by the transfection of apple fruit and/or calli with an MdERF2-overexpression (ERF2-OE) and MdERF2-interference (ERF2-AN) vector. In addition, the direct target genes of MdERF2 related to the biosynthesis of wax were identified using electrophoretic mobility shift assays (EMSAs) and dual-luciferase reporter assays (DLRs). The findings indicated that the levels of expression of the wax biosynthetic genes, including long-chain acyl-CoA synthetase 2 (MdLACS2), Eceriferum 1 (MdCER1), Eceriferum 4 (MdCER4), and Eceriferum 6 (MdCER6) were upregulated by ERF2-OE. In contrast, the levels of expression of these genes were inhibited when MdERF2 was silenced. Furthermore, the overall structure and accumulation of the fruit cuticular wax were influenced by the levels of expression of MdERF2. Treatment with ERF2-OE significantly increased the proportion of alkanes and ketones and reduced the proportion of fatty acids and esters. Additionally, the EMSAs and DLRs demonstrated that MdERF2 could bind directly to GCC-box elements in the promoters of MdLACS2, MdCER1, and MdCER6 to activate their transcription. These results confirm that MdERF2 targets the up-regulation of the levels of expression of MdLACS2, MdCER1, and MdCER6 genes, thereby altering the composition, content, and microstructure of apple epidermal wax.