Accurate modeling of the molecular environment is critical in condensed phase simulations of chemical reactions. Conventional quantum mechanical/molecular mechanical (QM/MM) simulations traditionally model non-electrostatic non-bonded interactions through an empirical Lennard-Jones (LJ) potential which, in violation of intuitive chemical principles, is bereft of any explicit coupling to an atom’s local electronic structure. This oversight results in a modelwhereby short-ranged exchange-repulsion and long-ranged dispersion interactions are invariant to changes in the local atomic charge, leading to accuracy limitations for chemical reactions where significant atomic charge transfer can occur along the reaction coordinate. The present work presents a variational, charge-dependent exchange-repulsion and dispersionmodel, referred to as the charge-dependent exchange and dispersion (QXD) model, for hybrid QM/MM simulations. Analytic expressions for the energy and gradients are provided, as well as a description of the integration of the model into existing QM/MM frameworks, allowing QXD to replace traditional LJ interactions in simulations of reactive condensed phase systems. After initial validation against QM data, the method is demonstrated by capturing the solvation free energies of a series of small, chlorine-containing compounds that have varying charge on the chlorine atom. The model is further tested on the SN2 attack of a chloride anion on methylchloride. Results suggest that the QXD model, unlike the traditional LJ model, is able to simultaneously obtain accurate solvation free energies for a range of compounds while at the same time closely reproducing the experimental reactionfree energy barrier. The QXD interaction model allows explicit coupling of atomic charge with many-body exchange and dispersion interactions that are related to atomic size and provides a more accurate and robust representation of non-electrostatic non-bonded QM/MM interactions.