The selective acylation of 2-methoxynaphthalene (2-MON) is commercially very important to produce selectively 2-acyl-6-methoxynaphthalene (2,6-AMON), which is a precursor to Naproxen, an anti-inflammatory drug. Most of the laboratory investigations conducted with different solid acids show that the undesirable products are formed in large quantities. Thus, various molecular modeling techniques were used to investigate selectivity towards desired 2,6-AMON isomer over undesired 1,2-AMON, in four large-pore zeolites, namely, mordenite (MOR), zeolite L (LTL), zeolite beta (BEA) and ITQ-7 (ISV). The qualitative results were obtained by using simple molecular graphics (MG) and structural fitting approach. The quantitative results were obtained by incorporating the interaction of atoms of the molecules and those of the zeolite frameworks. From diffusion energy profile calculations the diffusion energy barriers for self-diffusion of 2-MON and the acylated isomers were obtained. From these energy barrier values the selectivity offered by zeolites towards desired product was determined and it was found to be in the order of ISV>BEA>MOR>LTL. Hybrid Quantum Mechanics-Molecular Mechanics (QM/MM) approach was used to study the effect of Brønsted acidity on the activity and selectivity offered by zeolites. The interaction of the reactant and product species with the acidic protons at T3 and T9 sites in BEA, having different acidities was studied by this method. The QM energy values indicate that acidity affected the catalytic activity but not the regioselectivity towards the desired 2,6-AMON isomer.