The interacting quantum atoms (IQA) method decomposes the quantum mechanical (QM) energy of a molecular system in terms of one- and two-center (atomic) contributions within the context of the quantum theory of atoms in molecules. Here, we demonstrate that IQA, enhanced with molecular mechanics (MM) and Poisson-Boltzmann surface-area (PBSA) solvation methods, is naturally extended to the realm of hybrid QM/MM methodologies, yielding intra- and inter-residue energy terms that characterize all kinds of covalent and noncovalent bonding interactions. To test the robustness of this approach, both metal-water interactions and QM/MM boundary artifacts are characterized in terms of the IQA descriptors derived from QM regions of varying size in Zn(II)- and Mg(II)-water clusters. In addition, we analyze a homologous series of inhibitors in complex with a matrix metalloproteinase (MMP-12) by carrying out QM/MM-PBSA calculations on their crystallographic structures followed by IQA energy decomposition. Overall, these applications not only show the advantages of the IQA QM/MM approach but also address some of the challenges lying ahead for expanding the QM/MM methodology.