A new oral antiviral, obeldesivir (ODV), has shown effectiveness in protecting nonhuman primates (NHPs) against Sudan ebolavirus (SUDV). ODV, an oral prodrug of remdesivir (RDV), was tested in vitro and in a NHP model of SUDV infection. In the first study, ODV treatment for 10 days starting 1 day after SUDV exposure provided 100% protection against lethal infection. In the second study, 5 days of treatment provided 60% protection. Transcriptomics data showed that ODV treatment delayed inflammation and correlated with antigen presentation and lymphocyte activation. ODV is an RNA-dependent RNA polymerase inhibitor that is an oral alternative to parenterally administered RDV. It has shown activity against SARS-CoV-2 and is currently in phase 3 trials for COVID-19 treatment. In this study, ODV and its circulating parent nucleoside metabolite, GS-441524, showed similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and SUDV. The study found that ODV treatment delayed the onset of disease, suppressed viral replication, and prevented immune dysregulation and clotting abnormalities, thereby facilitating lymphocyte activation and the production of anti-SUDV antibodies. ODV treatment also prevented coagulopathy. The results support the further development of ODV for postexposure prophylaxis and treatment of filovirus infections. ODV has immediate potential for use in the management of filovirus outbreaks. The ease of supply, storage, distribution, and administration of oral antivirals compared with parenterally administered agents would facilitate timely initiation of both easily scalable postexposure prophylaxis and early disease treatment. These approaches could also help with broader acceptance and stronger support of medical countermeasures.A new oral antiviral, obeldesivir (ODV), has shown effectiveness in protecting nonhuman primates (NHPs) against Sudan ebolavirus (SUDV). ODV, an oral prodrug of remdesivir (RDV), was tested in vitro and in a NHP model of SUDV infection. In the first study, ODV treatment for 10 days starting 1 day after SUDV exposure provided 100% protection against lethal infection. In the second study, 5 days of treatment provided 60% protection. Transcriptomics data showed that ODV treatment delayed inflammation and correlated with antigen presentation and lymphocyte activation. ODV is an RNA-dependent RNA polymerase inhibitor that is an oral alternative to parenterally administered RDV. It has shown activity against SARS-CoV-2 and is currently in phase 3 trials for COVID-19 treatment. In this study, ODV and its circulating parent nucleoside metabolite, GS-441524, showed similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and SUDV. The study found that ODV treatment delayed the onset of disease, suppressed viral replication, and prevented immune dysregulation and clotting abnormalities, thereby facilitating lymphocyte activation and the production of anti-SUDV antibodies. ODV treatment also prevented coagulopathy. The results support the further development of ODV for postexposure prophylaxis and treatment of filovirus infections. ODV has immediate potential for use in the management of filovirus outbreaks. The ease of supply, storage, distribution, and administration of oral antivirals compared with parenterally administered agents would facilitate timely initiation of both easily scalable postexposure prophylaxis and early disease treatment. These approaches could also help with broader acceptance and stronger support of medical countermeasures.