QM-VM2, which efficiently combines statistical mechanics with quantum mechanical (QM) energy potentials in order to calculate noncovalent binding free energies of host–guest systems, is presented. QM-VM2 efficiently couples the use of semi-empirical QM (SEQM) energies and geometry optimizations with an underlying molecular mechanics (MM) based conformational search, to find low SEQM energy minima, and allows for processing of these minima at higher levels of ab initio QM theory. The newly implemented QM-VM2 is used to compute the binding free energies of the host molecule cucurbit[7]uril and a set of 15 guest molecules. See “Computation of host–guest binding free energies with a new quantum mechanics based mining minima algorithm” J. Chem. Phys. 154, 104122 (2021); doi: 10.1063/5.0040759