© 2014 American Chemical Society. Quantum mechanics/molecular mechanics (QM/MM) simulations provide an efficient avenue for studying reactions catalyzed in zeolite systems; however, the accuracy of such calculations is highly dependent on the zeolite MM parameters used. Previously reported parameters (P1), which were chosen to minimize the root mean square (RMS) deviations of adsorption energies compared with full QM ωB97X-D/6-31+G∗∗ adsorption energies, are shown to overestimate binding energies compared with experimental values, particularly for larger substrates. To address this issue, a new parameter set (P2) is derived by rescaling the previously reported characteristic energies of the Lennard-Jones potential in P1. The accuracy of the thermal correction for adsorption enthalpies determined by the rigid rotor-harmonic oscillator approximation (RRHO) is examined and shown to be improved by treating low-lying vibrational modes as free translational and rotational modes via a quasi-RRHO model. With P2 and quasi-RRHO, adsorption energies calculated with QM/MM agree with experimental values with an RMS error of 1.8 kcal/mol for both nonpolar and polar molecules adsorbed in MFI, H-MFI, and H-BEA. By contrast, the RMS error for the same test sets obtained using parameter set P1 is 8.3 kcal/mol. Glucose-fructose isomerization catalyzed by Sn-BEA is taken as an example to demonstrate that improved values for apparent activation energies can be obtained using the methodology reported here. With parameter set P2, the apparent activation energy calculated with QM/MM reproduces the experimental value to within 1 kcal/mol. By contrast, using parameter set P1, the error is -12.9 kcal/mol. (Graph Presented).