In the present study, we have comprehensively studied the impact of three widely used water models on the structure and reactivity of three CYP450 enzymes using MD simulations and hybrid QM/MM calculations. MD simulations show that the three water models, TIP3P, SPC/E, and OPC do not have much impact on the RMSD and RMSF values, however, the population of water and dipole moment depends upon the polarity of the active sites of the CYP450 enzymes. For instance, for hydrophobic active sites such as CYP450BM3, the TIP3P, and SPC/E water models have better water populations while for the polar active sites such as CYP450OleT and CYP450BSβ the OPC model performs well. Due to altered water count, the local dynamics in the active site such as Phe87 and substrate orientations in CYP450BM3 were found to be slightly different in OPC and it requires less conformational sampling with respect to TIP3P and SPC/E water models. The QM/MM calculations show that the TIP3P and OPC water models perform better than the SPC/E water model, although an accurate implementation of the fourth site of the OPC water model was not possible in the Chemshell program. In nutshell, TIP3P and SPC/E water models may perform better than the OPC model in the hydrophobic site while the OPC water model is recommended for the polar environments.