Voriconazole (VCZ) metabolism is influenced by many factors. Identifying independent influencing factors helps optimize VCZ dosing regimens and maintain its trough concentration (C) in the therapeutic window. We conducted a prospective study investigating independent factors influencing VCZ C and the VCZ C to VCZ N-oxide concentration ratio (C/C) in younger adults and elderly patients. A stepwise multivariate linear regression model, including the IL-6 inflammatory marker, was used. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive effect of the indicator. A total of 463 VCZ C were analyzed from 304 patients. In younger adult patients, the independent factors that influenced VCZ C were the levels of total bile acid (TBA) and glutamic-pyruvic transaminase (ALT) and the use of proton-pump inhibitors. The independent factors influencing VCZ C/C were IL-6, age, direct bilirubin, and TBA. The TBA level was positively associated with VCZ C ( = 0.176, = 0.019). VCZ C increased significantly when the TBA levels were higher than 10 μmol/L ( = 0.027). ROC curve analysis indicated that when the TBA level ≥4.05 μmol/L, the incidence of a VCZ C greater than 5 μg/ml (95% CI = 0.54-0.74) ( = 0.007) increased. In elderly patients, the influencing factors of VCZ C were DBIL, albumin, and estimated glomerular filtration rate (eGFR). The independent factors that affected VCZ C/C were eGFR, ALT, γ-glutamyl transferase, TBA, and platelet count. TBA levels showed a positive association with VCZ C ( = 0.204, = 0.006) and C/C ( = 0.342, < 0.001). VCZ C/C increased significantly when TBA levels were greater than 10 μmol/L ( = 0.025). ROC curve analysis indicated that when the TBA level ≥14.55 μmol/L, the incidence of a VCZ C greater than 5 μg/ml (95% CI = 0.52-0.71) ( = 0.048) increased. TBA level may serve as a novel marker for VCZ metabolism. eGFR and platelet count should also be considered when using VCZ, especially in elderly patients.