Treatment of breastfeeding mothers with malaria is challenging due to the lack of information describing drug exposure in milk and the daily dose to the breastfed infant. Physiologically based pharmacokinetic (PBPK) modeling was used to predict milk-to-plasma (M/P) ratios, infant daily doses (IDD) and relative infant doses (RID) for five antimalarials with clinical lactation data (chloroquine, pyrimethamine, piperaquine, mefloquine and primaquine). In all cases, RID was correctly categorized as above or below the WHO proposed cut-off of 10% using two prediction models. Predicted M/P ratios were within 2-fold of observations for 63% of studies using both models (75% and 100% were within 3-fold for Models 1 and 2, respectively). M/P ratios, IDD and RID were predicted prospectively for seven antimalarials. RID was <
10% for amodiaquine, dihydroartemisinin, proguanil, and pyronaridine, and >
10% for lumefantrine and tafenoquine. For atovaquone, RID was >
10% with Model 1 but not Model 2. Predicted IDD were considerably lower than licensed doses for infants except for lumefantrine (Model 2) and tafenoquine (not licensed in <
2 years). Predictions were sensitive to drug properties (plasma protein binding and lipophilicity) and milk properties (creamatocrit and pH). This analysis demonstrates the utility of PBPK to predict milk exposure in the absence of clinical lactation information. These prediction methodologies can be used, alongside any licensed dosing information for <
1 year-olds, to evaluate whether a clinical lactation study is necessary and to inform drug label or policy recommendations. The ultimate goal is to better inform optimal treatment for lactating women supporting malaria eradication.