Amoxicillin is commonly used to treat erythema migrans in the first stage of Lyme disease in children, with a recommended dose of 50 mg/kg/day, administered three times a day (q8h). This model-based simulation study aimed to determine whether splitting the same daily dose into two administrations (q12h) would provide comparable drug exposure. A pharmacokinetic model suitable for a pediatric population (age: 1 month to 18 years, weight: 4-80 kg) was selected through a literature review. Simulations were performed with 15,000 virtual patients receiving 16.67 mg/kg/dose q8h, 25 mg/kg/dose q12h, or other q12h dosing variations. The target therapeutic level was defined by the percentage of time that the unbound drug concentration remained above the minimum inhibitory concentration (% fT > MIC) specific to Borrelia burgdorferi, with MICs of 0.06, 0.25, 1, 2, and 4 mg/L, requiring at least 40% and 50% of time for effective treatment. Probability of target attainment (PTA) was considered acceptable if it exceeded 50%, allowing for comparison of dosing schedules. Results indicated that the 50 mg/kg/day divided q12h regimen provided similar drug exposure to the q8h regimen for MICs below 2 mg/L (PTAs >50%). For a MIC of 2 mg/L, PTA was achieved with a higher dose of 30 mg/kg/dose q12h. However, for a MIC of 4 mg/L, the PTA criterion was not met. These findings suggest that a twice-daily dosing of 25 mg/kg/dose provides comparable bactericidal activity to the thrice-daily regimen for MICs between 0.06 and 1 mg/L. This simplified regimen may improve adherence and treatment implementation in children.