Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 μM IC₅₀) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC₅₀) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections.