Mathematical modeling of pharmacokinetic (PK) and pharmacodynamic (PD) parameters essential for establishing correct dosing regimens is an alternative to pharmacokinetic studies (PKS) adopted in the clinical setting. The aim of this work was to compare the values of PK parameters for vancomycin obtained in an actual PKS and through MM in postoperative patients with kidney injury. Our prospective study included 61 patients (47 males and 14 females aged 60.59 ± 12.23 years). During PKS, drug concentrations at steady state С_trough and C_peak were measured by high-performance liquid chromatography followed by the calculation of the area under the plasma concentration-time curve AUC₂₄. For mathematical modeling, a single-compartment model was employed; PK parameters were estimated using R 3.4.0. The values of C_trough measured 48 h after the onset of antibiotic therapy during PKS were significantly lower than those predicted by MM (р = 0.004). In a group of patients with acute kidney injury (AKI), AUC₂₄ measured at the end of treatment was significantly higher than its value predicted by MM (р = 0.011). The probability of achieving the target AUC₂₄ to MIC ratio of over 400 μg•h /ml is higher in the group of patients with C_trough = 10–15 μg /ml. Our findings confirm that the use of MM in postoperative patients with renal dysfunction is limited and therapeutic drug monitoring should be used instead.