Background A newer malaria preventive treatment, dihydroartemisinin-piperaquine (DP), has been identified as an effective alternative to sulfadoxine-pyrimethamine, to which malaria parasites are increasingly becoming resistant. However, how best to dose DP to safely prevent malaria in infants when aligned with routine health facility visits remains unresolved. As infants are usually excluded from participating in early dose optimisation clinical trials, the present study seeks to shift the paradigm and develop optimised DP dosing strategies for malaria preventive treatment in infants. Methods A randomised, single-blind, placebo-controlled, two-arm, interventional study will be conducted in southern Malawi. At 10 weeks (2.5 months) of age, 220 eligible infants will be randomised to receive DP (intervention group, n=110) or placebo (control group, n=110) with routine vaccines. They will be followed until 12 months of age and receive three further DP or placebo treatment courses at 14 weeks, six- and nine months. Infants in the intervention group will contribute capillary samples for piperaquine concentrations pre-dose and at three-, seven-, 14- and 28-days post-DP dosing as well as capillary samples pre-dose and on day 28 post-DP to quantify malaria parasitaemia using microscopy and quantitative PCR. In the control group, infants will contribute capillary blood samples for malaria parasitaemia at the same time points as the intervention group. Malaria incidence and adverse events will be compared between the two groups. Population pharmacokinetic-pharmacodynamic modelling techniques will be applied to derive feasible, optimised, efficacious, and safe DP dosing strategies for malaria preventive treatment in infancy. Conclusions The findings will provide the much-needed evidence to inform DP dosing for malaria preventive treatment in infants when administered with routine health facility visits. Additionally, they will help inform optimal DP dosing for malaria treatment in infants. The trial was registered with the Pan African Clinical Trials Registry; (PACTR202211575727659) on 8 November 2022. Protocol version 3.1, dated 29 September 2022.