Molecular dynamics (MD) simulations based on atomic models play an important role in the drug-discovery process to screen molecules, estimate binding free energies, and optimize lead compounds in chemical space. Accurate computations of thermodynamic and kinetic properties using MD simulations are highly dependent on the accuracy of the underlying atomic force field. In this context, going beyond the nonpolarizable fixed-charge model by accounting explicitly for induced polarization is highly desirable. The CHARMM polarizable force field based on classical Drude oscillators, in which an auxiliary charged particle is attached via a harmonic spring to its parent nucleus, offers both a computationally convenient and rigorous framework to model explicitly induced electronic polarization in MD simulations. For any molecule of interest, electrostatic partial charges, atomic polarizabilities, and Thole shielding factors, as well as bonded parameters can either be determined from ab initio calculations or ascribed from the knowledge-based library of the CHARMM Generalized force field. While this approach is fairly reliable in general, it is well understood that the overall accuracy of the models with respect to thermodynamic properties such as bulk density, enthalpies, and solvation free energies is particularly sensitive to the nonbonded Lennard-Jones (LJ) parameters. In the present study, we systematically refined the set of LJ parameters for the atom types available in the Drude force field to best match the experimental thermodynamic properties for 416 small druglike organic molecules. To further test the transferability of the optimized parameters, the hydration free energy of 372 molecules was computed. The calculations resulted in a small average error of 0.46 kcal/mol and a Pearson R of 0.9, representing a significant improvement over the additive GAFF force field in our previous study, where an average error of ∼2 kcal/mol was obtained. Such an improvement is consistent with the ability of the polarizable Drude model to more accurately model interactions in different environments. The effort provides a roadmap for the global optimization of force field parameters using experimental data. It is hoped that the present effort will further the application of the Drude polarizable force field in molecular simulations including drug design and discovery.