Fluorescent semiconductor nanocrystals possess a number of unique optical and chemical properties. These features make them useful fluorescent labels for applications in cell biology that require highly sensitive imaging. However, the development of new nanoparticle platforms that combine effective magnetic and optical properties remains a challenging task. Quantum mechanical modeling is an effective method for understanding the energetics of processes in nanostructures and improving synthesis technology. The cluster approach, for example, implemented using the Q-chem software package, allowed the modeling of structures with oxygen incorporation into sulfur positions. To assess the parameters of semiconductor materials, a comparison of the efficiency and features of quantum–mechanical and quantum-chemical methods was conducted using the example of sphalerite structure modeling with oxygen impurities. The quantum-chemical approach allows for the modeling of the necessary defect structure of any complexity, with the results better reflecting the real picture than the QUANTUM ESPRESSO method. As a result of using Q-chem, splitting of energy bands near the top of the valence band and the bottom of the conduction band was observed. A method for controlling the fluorescence properties of zinc sulfide-based semiconductor nanoparticles activated by oxygen has been demonstrated.