Cytochrome P450 (CYP) enzymes are responsible for oxidative metabolisms of a large number of xenobiotics. In this study, we investigated interactions of silver nanoparticles (AgNPs) and silver ions (Ag+) with six CYP isoforms, namely, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, within CYP-specific inhibitor-binding pockets by molecular docking and quantum mechanical (QM) calculations. The docking results revealed that the Ag3 cluster, not Ag+, interacted with key amino acids of CYP2C9, CYP2C19, and CYP2D6 within a distance of about 3 Å. Moreover, the QM analysis confirmed that the amino acid residues of these CYP enzymes strongly interacted with the Ag3 cluster, providing more insight into the mechanism of the potential inhibition of CYP enzyme activities. Interestingly, these results are consistent with previous in vitro data indicating that AgNPs inhibited activities of CYP2C and CYP2D in rat liver microsomes. It is suggested that the Ag3 cluster is a minimal unit of AgNPs for in silico modeling. In summary, we demonstrated that molecular docking, together with QM analysis, is a promising tool to predict AgNP-mediated CYP inhibition. These methods are useful for deeper understanding of reaction mechanisms and could be used for other nanomaterials.