The unprecedented magnitude of the 2013–2016 Ebola virus (EBOV) epidemic in West Africa resulted in over 11 000 deaths and spurred an international public health emergency. A second outbreak in 2018–2020 in DRC resulted in an additional >3400 cases and nearly 2300 deaths (WHO, 2020). These large outbreaks across geographically diverse regions highlight the need for the development of effective oral therapeutic agents that can be easily distributed for self-administration to populations with active disease or at risk of infection. Herein, we report the in vivo efficacy of N⁴-hydroxycytidine (EIDD-1931), a broadly active ribonucleoside analog and the active metabolite of the prodrug EIDD-2801 (molnupiravir), in murine models of lethal EBOV infection. Twice daily oral dosing with EIDD-1931 at 200 mg/kg for 7 days, initiated either with a prophylactic dose 2 h before infection, or as therapeutic treatment starting 6 h post-infection, resulted in 92–100% survival of mice challenged with lethal doses of EBOV, reduced clinical signs of Ebola virus disease (EVD), reduced serum virus titers, and facilitated weight loss recovery. These results support further investigation of molnupiravir as a potential therapeutic or prophylactic treatment for EVD.