Study Objective: Treatment of HIV and tuberculosis co‐infection leads to significant mortality in pediatric patients, and treatment can be challenging due to the clinically significant drug–drug interaction (DDI) between lopinavir/ritonavir (LPV/RTV) and rifampin. Doubling LPV/RTV results in insufficient lopinavir trough concentrations in pediatric patients. The objective of this study was to leverage physiologically based pharmacokinetic (PBPK) modeling to optimize the adjusted doses of LPV/RTV in children receiving the WHO‐revised doses of rifampin (15 mg/kg daily). Design: Adult and pediatric PBPK models for LPV/RTV with rifampin were developed, including CYP3A and P‐glycoprotein inhibition and induction. Setting (or Data Source): Data for LPV/RTV model development and evaluation were available from the pediatric AIDS Clinical Trials Group. Patients Dosing simulations were next performed to optimize dosing in children (2 months to 8 years of age). Intervention: Exposure following super‐boosted LPV/RTV with 10 and 15 mg/kg PO daily rifampin was simulated. Measurements and Main Results: Simulated parameters were within twofold observations for LPV, RTV, and rifampin in adults and children ≥2 weeks old. The model predicted that, in healthy adults receiving 400/100 mg oral LPV/RTV twice daily (BID), co‐treatment with 600 mg oral rifampin daily decreased the steady‐state area under the concentration vs. time curve of LPV by 79%, in line with the observed change of 75%. Simulated and observed concentration profiles were comparable for LPV/RTV (230/57.5 mg/m2) PO BID without rifampin and 230/230 mg/m2 LPV/RTV PO BID with 10 mg/kg PO daily rifampin in pediatric patients. Sixteen mg/kg of super‐boosted LPV (LPV/RTV 1:1) PO BID with 15 mg/kg PO daily rifampin achieved simulated LPV troughs >1 mg/L in ≥93% of virtual children weighing 3.0‐24.9 kg, which was comparable with 10 mg/kg PO daily rifampin. Conclusions: Super‐boosted LPV/RTV with 15 mg/kg rifampin achieves therapeutic LPV troughs in HIV/TB‐infected simulated children. [ABSTRACT FROM AUTHOR]