Background: Equine arteritis virus (EAV) induces extensive vascular endothelium damage that can lead to abortion, neonatal death, reduced fertility, or loss of performance. Of the two vaccines currently on market, only the inactivated one is ANMV-approved (French Agency for Veterinary Medicinal Products) in Europe. Since 2023, vaccine supply delays or unavailability have been source of great concern in the equine industry. Since no curative treatment for EAV is currently marketed, finding other solutions to limit the viral spread such as antiviral molecules are needed. Our previous work showed that Ribavirin impairs the EAV-replication in vitro in equine dermal cells (EDc) [1] which made us confident of finding other anti-EAV molecules with a lower cytotoxic and higher anti-EAV profile. Objective: To identify candidate compounds through drug repositioning and library screening which is quicker and cost-saving compared to de novo drug discovery. Study design: In vitro experiments. Methods: Three libraries were screened using a high-throughput in cellulo phenotypic-based protocol on their cytotoxicity and cytoprotective capabilities in EDc. Results: Out of more than 3000 molecules, 92 were identified as hit ones, and for 80 of them we confirmed their capability to decrease the EAV production in vitro. Most of the molecules already on market (with known mechanisms of action) seem to target ionic channel blockade and lipid metabolism modulation; both pathways are already known to impact viral replication of other Nidovirales virus such as SARS-CoV-2. Main limitation: Results need to be confirmed. Conclusion: These new molecules, showing antiviral capacities or expanding their antiviral spectrum, have been included in a translational global health research project to look for their antiviral capacity against other animal or human viruses (SARS-CoV-2, FCoV). Through the study of equine infectious disease, this project will increase the number of antiviral molecules that could be of use in future pandemics. Ethical animal research: Not applicable. Informed consent: Not applicable. Competing interests: None declared. Funding: Supported by the Normandy region and the European Union with the European Regional Development Fund (FEDER). Reference: [1] Valle-Casuso J-C, Gaudaire D, Martin-Faivre L, Madeline A, Dallemagne P, Pronost S, Munier-Lehmann H, Zientara S, Vidalain P-O, Hans A. Replication of equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors. Sci Rep. 2020;10(1):10100. doi: 10.1038/s41598-020-66944-4