AbstractCefazolin is an antibiotic used to prevent surgical site infections. During cardiac surgery with cardiopulmonary bypass (CPB), its efficacy target could be underachieved. We aimed to develop a population pharmacokinetic model for cefazolin in children and optimize the prophylactic dosing regimen. Children under 25 kg undergoing cardiac surgery with CPB and receiving cefazolin at standard doses (50 mg/kg IV every 4–6 h) were included in this analysis. A population pharmacokinetic model and Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) for efficacy and toxicity with the standard regimen and an alternative regimen of continuous infusion, where loading and maintenance doses were calculated from model‐derived individual parameters. Twenty‐two patients were included, with median (range) age, body weight, and eGFR of 19.5 (1–94) months, 8.7 (2–21) kg, and 116 (48–159) mL/min, respectively. Six patients received an additional dose in the CPB circuit. A two‐compartment disposition model with an additional compartment for the CPB was developed, including weight‐based allometric scaling and eGFR. For a 10 kg patient with eGFR of 120 mL/min/1.73 m², clearance was estimated as 0.856 L/h. Simulations indicated that the standard dosing regimen fell short of achieving the efficacy target >40% of the time within a dosing duration and in patients with good renal function, PTA ranged from <20% to 70% for the smallest to the largest patients, respectively, at high MICs. In contrast, the alternative regimen consistently maintained target concentrations throughout the procedure for all patients while using a lower overall dose.