We theoretically explore the influence of end-group chemistry (bond stiffness and mass) on the interfacial thermal conductance at a gold–alkane interface. We accomplish this using the nonequilibrium Green’s function (NEGF) coupled with first principle parameters in density functional theory (DFT) within the harmonic approximation. Our results indicate that the interfacial thermal conductance is not a monotonic function of either chemical parameters but instead maximizes at an optimal set of mass and bonding strength. This maximum is a result of the interplay between the overlap in local density of states (LDOS) of the device and that in the contacts, as well as the phonon group velocity. We also demonstrate the intrinsic relationship between the diffusive mismatch model (DMM) and the properties from NEGF, and provide an approach to get DMM from first principles NEGF. By comparing the NEGF-based DMM conductance and range of conductance while altering the mass and bonding strength, we show that DMM provides an upper bound for elastic transport in this dimension-mismatched system. We thus have a prescription to enhance the thermal conductance of systems at low temperatures or at low dimensions where inelastic scattering is considerably suppressed.