Aim: Appropriate drug exposure is as crucial as proper selection and timely antibiotic administration in sepsis treatment. However, evidence is lacking regarding the current dosing regimen to achieve pharmacodynamic targets in patients with sepsis. This study aimed to describe ceftriaxone pharmacokinetic (PK) parameters and establish optimal dosing regimens for sepsis patients. Methods: This study investigated the pharmacokinetics of ceftriaxone in sepsis patients receiving ceftriaxone 2 g every 12 or 24 h. Blood samples (11–14 samples per patient) were collected within the first 24 h post-administration. PK parameters were estimated from unbound plasma concentrations using a non-linear mixed-effects modelling approach (NONMEM® software). Monte Carlo simulations were conducted to evaluate the probability of target attainment of standard and high-dose ceftriaxone at various minimum inhibitory concentrations (MICs). Results: Population PK analysis of 238 concentration-time data points from 20 patients revealed that a two-compartment model best described ceftriaxone PK. Glomerular filtration rate (GFR), serum albumin, and body weight significantly affected clearance, volume of distribution, and intercompartmental clearance, respectively. Simulation results demonstrated that the standard dose of 2 g every 24 h was adequate for pathogens with MIC ≤1 mg L -1. For pathogens with higher MICs (2–8 mg L -1), particularly in patients with GFR >130 mL min -1, a dose of 2 g every 12 h may be more appropriate. Conclusion: Standard ceftriaxone (2 g intravenous q 24 h, 30-min infusion) was adequate for susceptible pathogens, whereas modified regimens were warranted for patients infected with less susceptible organisms with augmented renal clearance.