question: As the toll of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues, efforts are ongoing to identify new agents and repurpose safe drugs for its treatment. Antimalarial peroxides have reported antiviral and anticancer activities. Here, we evaluated the in vitro activities of artesunate (AS) and two ozonides (OZ418 and OZ277) against human &#945;-coronavirus NL63 and ß-coronaviruses OC43 and SARS-CoV-2 in several cell lines. OZ418 had the best selectivity index (SI) in NL63-infected Vero cells and MK2 cells. The overall SI of the tested compounds was cell-type dependent. In OC43-infected human foreskin fibroblasts, AS had the best cell-associated SI, &#8805;17 µM, while the SI of OZ418 and OZ277 was &#8805;12 µM and &#8805;7 µM, respectively. AS did not inhibit SARS-CoV-2 in either Vero or Calu-3 cells. A comparison of OZ418 and OZ277 activity in SARS-CoV2-infected Calu-3 cells revealed similar EC50 (5.3 µM and 11.6 µM, respectively), higher than the EC50 of remdesivir (1.0 ± 0.1 µM), but the SI of OZ418 was higher than OZ277. A third ozonide, OZ439, inhibited SARS-CoV-2 efficiently in Vero cells, but compared to OZ418 in Calu-3 cells, it showed higher toxicity. Improved inhibition of SARS-CoV-2 was observed when OZ418 was used together with remdesivir. Although the EC50 of ozonides might be clinically achieved in plasma after intravenous administration, sustained virus suppression in tissues will require further considerations, including drug combination. Our work supports the potential repurposing of ozonides and calls for future in vivo models.