A new experimental-computational strategy for the determination of the absolute configuration (AC) of complex chiral molecules is proposed by combining diverse experimental spectroscopies with quantum-mechanical simulations well beyond the current computational practice. Key features are the conformer search and relative stability evaluation performed by a new stochastic two-level tool followed by a vis-à-vis comparison of experimental and computed spectra without any ad hoc adjustment. The entire computational procedure is embedded in the user-friendly VMS software, and its reliability is granted by the inclusion of mechanic/electric/magnetic anharmonicity as well as ro-vibrational and vibronic couplings by means of generalized perturbation theory in conjunction with double-hybrid functionals combined with empirical dispersion contributions and suitable basis sets. To test and validate the new approach, the puzzling case of diplopyrone, a fungal phytotoxic metabolite, has been chosen: the close match between new experimental and simulated infrared absorption and vibrational circular dichroism spectra has led to the unbiased evaluation of its AC.