There are no effective therapies for patients with coronavirus disease-2019 (COVID-19). Forty-one patients with confirmed COVID-19 were enrolled in the study and divided into two groups: artemisinin-piperaquine (AP) (n = 23) and control (n = 18). The primary outcome were the time taken to reach undetectable levels of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and the percentage of participants with undetectable SARS-CoV-2 on days 7, 10, 14, and 28. The computed tomography (CT) imaging changes within 10 days, corrected QT interval changes, adverse events, and abnormal laboratory parameters were the secondary outcomes. The mean time to reach undetectable viral RNA (mean ± standard deviation) was 10.6 ± 1.1 days (95% confidence interval [CI] 8.4-12.8) for the AP group and 19.3 ± 2.1 days (95% CI 15.1-23.5) for the control group. The percentages of patients with undetectable viral RNA on days 7, 10, 14, 21, and 28 were 26.1%, 43.5%, 78.3%, 100%, and 100%, respectively, in the AP group and 5.6%, 16.7%, 44.4%, 55.6%, and 72.2%, respectively, in the control group. The CT imaging within 10 days post-treatment showed no significant between-group differences (P > 0.05). Both groups had mild adverse events. In patients with mild-to-moderate COVID-19, the time to reach undetectable SARS-CoV-2 was significantly shorter in the AP group than that in the control group. However, physicians should consider QT interval changes before using AP. Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.