Fluconazole, a triazole antifungal drug predominantly cleared unchanged by the kidney, shows wide pharmacokinetic (PK) variability in patients with impaired renal function or undergoing renal replacement therapy (RRT). These alterations can critically influence antifungal efficacy and safety, necessitating individualized dosing approaches. This study investigated how renal dysfunction and different RRT modalities—including continuous veno-venous hemofiltration (CVVHF), hemodiafiltration (CVVHDF), and peritoneal dialysis (PD)—modify the PK behavior of fluconazole. By comparing key PK parameters across populations, we sought to identify clinically relevant alterations and propose dosing strategies tailored to patient condition. Clinical PK data of fluconazole were collected from human studies and standardized for cross-population analysis. Parameters including area under the curve (AUC), maximum plasma concentration (C_max), clearance (CL), volume of distribution (V_d), and elimination half-life (T½) were evaluated according to renal function and dialysis modality. Dose proportionality and PK variability were assessed under equivalent dosing regimens. Fluconazole maintained linear PK in healthy individuals, whereas critically ill and renally impaired patients exhibited non-linear and highly variable PK. In severe renal impairment (GFR < 20 mL/min), clearance decreased more than five-fold and T½ extended over three-fold compared to normal renal function. In contrast, patients on continuous RRT showed enhanced drug elimination, with CVVHDF producing the highest clearance values, though interindividual variability remained significant depending on dialyzer characteristics and flow rates. Across identical intravenous doses, AUC varied more than two-fold and T½ up to three-fold between groups, demonstrating that both physiological condition and extracorporeal modality strongly influence systemic exposure. Fluconazole pharmacokinetics are profoundly altered by renal dysfunction and dialysis. Standard dosing regimens derived from healthy subjects are insufficient in these populations. Adjustments based on creatinine clearance and dialysis modality, supported by therapeutic drug monitoring when available, are essential to achieve effective antifungal therapy while minimizing toxicity.