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Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV–related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease. Editor's summary: Currently approved antivirals for SARS-CoV-2 target one of two viral proteins. Remdesivir and molnupiravir target the RNA-dependent RNA polymerase (RdRp), whereas nirmatrelvir (the antiviral agent of Paxlovid) targets the main protease (Mpro). Although these drugs are effective, there continues to be room for improvement, especially for drugs targeting the RdRp. Here, Martinez et al. evaluated the efficacy of an orally available small-molecule targeting the RdRp of SARS-CoV-2 and other coronaviruses called GS-5245 or obeldesivir. The authors found that GS-5245 could reduce disease severity in mice infected with one of several different coronaviruses, including SARS-CoV-2, SARS-CoV, and MERS-CoV. Moreover, combining GS-5245 with nirmatrelvir further improved outcomes in mice infected with SARS-CoV-2. Together, these data support further development of GS-5245/obeldesivir as a broader anti-coronaviral drug. —Courtney Malo [ABSTRACT FROM AUTHOR]