Imidazole is a five‐membered heterocycle that is part of a number of biologically important molecules such as the amino acid histidine and the hormone histamine. Imidazole has a unique ability to participate in a variety of non‐covalent interactions involving the NH group, the pyridine‐like nitrogen atom or the π‐system. For many biologically active compounds containing the imidazole moiety, its participation in formation of hydrogen bond NH⋯O/N and following proton transfer is the key step of mechanism of their action. In this work a systematic study of the mutual influence of various paired combinations of non‐covalent interactions (e.g., hydrogen bonds and π‐interactions) involving the imidazole moiety was performed by means of quantum chemistry (PW6B95‐GD3/def2‐QZVPD) for a series of model systems constructed based on analysis of available x‐ray data. It is shown that for considered complexes formation of additional non‐covalent interactions can only enhance the proton‐donating ability of imidazole. At the same time, its proton‐accepting ability can be both enhanced and weakened, depending on what additional interactions are added to a given system. The mutual influence of non‐covalent interactions involving imidazole can be classified as weak geometric and strong energetic cooperativity—a small change in the length of non‐covalent interaction formed by imidazole can strongly influence its strength. The latter can be used to develop methods for controlling the rate and selectivity of chemical reactions involving the imidazole fragment in larger systems. It is shown that the strong mutual influence of non‐covalent interactions involving imidazole is due to the unique ability of the imidazole ring to effectively redistribute electron density in non‐covalently bound systems with its participation. The possibilities of tuning the strength of hydrogen bonds involving the imidazole ring through the formation of additional non‐covalent interactions have been systematically studied.