Objectives: To develop a mechanism-based model that describes the time course of the malaria parasite in infected mice receiving a combination therapy regimen of dihydroartemisinin and piperaquine. Methods: Total parasite density-time data from Swiss mice inoculated with Plasmodium berghei were used for the development of population models in S-ADAPT. The mice were administered a single intraperitoneal dose of 30 mg/kg dihydroartemisinin, 10 mg/kg piperaquine phosphate or a combination of both antimalarials at 64 h post-inoculation. In a separate study, mice received multiple dihydroartemisinin doses (5×10 mg/kg or 30 mg/kg dihydroartemisinin followed by two 10 mg/kg doses). Parasite recrudescence after treatmentwas defined using a model that incorporated each erythrocytic stage of the P. berghei life cycle. Results: The disposition of dihydroartemisinin and piperaquine was described by a one-compartment and twocompartment model, respectively. The estimated clearance was 1.95 L/h for dihydroartemisinin and 0.109 L/h for piperaquine. A turnover model described the parasite killing curve after single-agent dosing, with an estimated mean IC50 of 0.747 μg/L for dihydroartemisinin and 16.8 μg/L for piperaquine. In addition, the rate of parasite killing by dihydroartemisinin was almost 50-fold faster than for piperaquine. Parameters from the monotherapy models adequately described the parasite density-time curve following dihydroartemisinin/piperaquine combination therapy or multiple-dose regimens of dihydroartemisinin. Conclusions: This study has developed mechanistic models that describe the parasite-time curve after single, multiple or combination dosing of antimalarials to mice. These structural models have potential application for pre-clinical investigations to design and refine artemisinin-based combination therapy dosage regimens. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.