We propose a fully-automated composite scheme for the accurate and numerically stable calculation of molecular entropies by efficiently combining density-functional theory (DFT), semi-empirical methods (SQM), and force-field (FF) approximations. The scheme is systematically expandable and can be integrated seamlessly with continuum-solvation models. Anharmonic effects are included through the modified rigid-rotor-harmonic-oscillator (msRRHO) approximation and the Gibbs–Shannon formula for extensive conformer ensembles (CEs), which are generated by a metadynamics search algorithm and are extrapolated to completeness. For the first time, variations of the ro-vibrational entropy over the CE are consistently accounted-for through a Boltzmann-population average. Extensive tests of the protocol with the two standard DFT approaches B97-3c and B3LYP-D3 reveal an unprecedented accuracy with mean deviations <1 cal mol⁻¹ K⁻¹ (about <1–2%) for the total gas phase molecular entropy of medium-sized molecules. Even for the hardship case of extremely flexible linear alkanes (C₁₄H₃₀–C₁₆H₃₄), errors are only about 3 cal mol⁻¹ K⁻¹. Comprehensive tests indicate a relatively strong variation of the conformational entropy on the underlying level of theory for typical drug molecules, inferring the complex potential energy surfaces as the main source of error. Furthermore, we show some application examples for the calculation of free energy differences in typical chemical reactions.