The Cope elimination reactions for threo- and erythro-N,N-dimethyl-3-phenyl-2-butylamine oxide have been investigated using QM/MM calculations in water, THF, and DMSO. The aprotic solvents provide up to million-fold rate accelerations. The effects of solvation on the reactants, transition structures, and rates of reaction are elucidated here using two-dimensional potentials of mean force (PMF) derived from free-energy perturbation calculations in Monte Carlo simulations (MC/FEP). The resultant free energies of activation in solution are in close agreement with experiment. Ab initio calculations at the MP2/6-311+G-(2d, p) level using the PCM continuum solvent model were also carried out; however, only the QM/MM methodology was able to reproduce the large rate increases in proceeding from water to the dipolar aprotic solvents. Solute-solvent interaction energies and radial distribution functions are also analyzed and show that poorer solvation of the reactant in the aprotic solvents is primarily responsible for the observed rate enhancements. It is found that the amine oxide oxygen is the acceptor of three hydrogen bonds from water molecules for the reactant but only one to two weaker ones at the transition state. The overall quantitative success of the computations supports the present QM/MM/MC approach, featuring PDDG/PM3 as the QM method.