Mass drug administration (MDA) of sequential rounds of antimalarial drugs is being considered for use as a tool for malaria elimination. As an effective and long-acting antimalarial, dihydroartemisinin-piperaquine (DHA-PQP) appears to be suitable as a candidate for MDA. However, the absence of cardiac safety data following repeated administration hinders its use in the extended schedules proposed for MDA. We conducted an interventional study in Lihir Island, Papua New Guinea, using healthy individuals age 3 to 60 years who received a standard 3-day course of DHA-PQP on 3 consecutive months. Twelve-lead electrocardiography (ECG) readings were conducted predose and 4 h after the final dose of each month. The primary safety endpoint was QT interval correction (QTc using Fridericia's correction [QTcF]) prolongation from baseline to 4 h postdosing. We compared the difference in prolongations between the third course postdose and the first course postdose. Of 84 enrolled participants, 69 (82%) participants completed all treatment courses and ECG measurements. The average increase in QTcF was 19.6 ms (standard deviation [SD], 17.8 ms) and 17.1 ms (SD, 17.1 ms) for the first-course and third-course postdosing ECGs risk difference, -2.4 (95% confidence interval [95% CI], -6.9 to 2.1; = 0.285), respectively. We recorded a QTcF prolongation of >60 ms from baseline in 3 (4.3%) and 2 (2.9%) participants after the first course and third course ( = 1.00), respectively. No participants had QTcF intervals of >500 ms at any time point. Three consecutive monthly courses of DHA-PQP were as safe as a single course. The absence of cumulative cardiotoxicity with repeated dosing supports the use of monthly DHA-PQP as part of malaria elimination strategies.