The study investigates the efficacy of obledesivir (ODV), an oral antiviral, against Sudan ebolavirus (SUDV) in nonhuman primates (NHPs). ODV, an RNA-dependent RNA polymerase inhibitor, was found to have similar in vitro antiviral activity against SUDV, Ebola virus (EBOV), and Marburg virus. In two NHP studies, ODV was administered orally to cynomolgus monkeys 24 hours after SUDV exposure. The first study showed that once-daily oral ODV treatment for 10 days confers 100% protection against lethal SUDV infection, while the second study found that a 5-day treatment regimen provided 60% protection. Transcriptomic analysis revealed that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. The results support further development of ODV for postexposure prophylaxis and treatment of filovirus infections, particularly in resource-poor settings where intravenous therapy is challenging. The ease of administration and supply of oral antivirals could facilitate timely and scalable interventions to control filovirus outbreaks.The study investigates the efficacy of obledesivir (ODV), an oral antiviral, against Sudan ebolavirus (SUDV) in nonhuman primates (NHPs). ODV, an RNA-dependent RNA polymerase inhibitor, was found to have similar in vitro antiviral activity against SUDV, Ebola virus (EBOV), and Marburg virus. In two NHP studies, ODV was administered orally to cynomolgus monkeys 24 hours after SUDV exposure. The first study showed that once-daily oral ODV treatment for 10 days confers 100% protection against lethal SUDV infection, while the second study found that a 5-day treatment regimen provided 60% protection. Transcriptomic analysis revealed that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. The results support further development of ODV for postexposure prophylaxis and treatment of filovirus infections, particularly in resource-poor settings where intravenous therapy is challenging. The ease of administration and supply of oral antivirals could facilitate timely and scalable interventions to control filovirus outbreaks.