We evaluated the population-level benefits of expanding treatment with the antiviral drug Paxlovid (nirmatrelvir/ritonavir) in the United States for SARS-CoV-2 Omicron variant infections. Using a multiscale mathematical model, we found that treating 20% of symptomatic case-patients with Paxlovid over a period of 300 days beginning in January 2022 resulted in life and cost savings. In a low-transmission scenario (effective reproduction number of 1.2), this approach could avert 0.28 million (95% CI 0.03–0.59 million) hospitalizations and save US $56.95 billion (95% CI US $2.62–$122.63 billion). In a higher transmission scenario (effective reproduction number of 3), the benefits increase, potentially preventing 0.85 million (95% CI 0.36–1.38 million) hospitalizations and saving US $170.17 billion (95% CI US $60.49–$286.14 billion). Our findings suggest that timely and widespread use of Paxlovid could be an effective and economical approach to mitigate the effects of COVID-19.