BACKGROUND: Non-pharmaceutical interventions (NPIs) are mitigation strategies used to reduce the spread of transmissible diseases. The relative effectiveness of specific NPIs remains uncertain. METHODS: We used state-level Coronavirus disease 2019 (COVID-19) case and mortality data between January 19, 2020 and March 7, 2021 to model NPI policy effectiveness. Empirically derived breakpoints in case and mortality velocities were used to identify periods of stable, decreasing, or increasing COVID-19 burden. The associations between NPI adoption and subsequent decreases in case or death velocities were estimated using generalized linear models accounting for weekly variability shared across states. State-level NPI policies included: stay at home order, indoor public gathering ban (mild >10 or severe â‰¤10), indoor restaurant dining ban, and public mask mandate. RESULTS: 28,602,830 cases and 511,899 deaths were recorded. The odds of a decrease in COVID-19 case velocity were significantly elevated for stay at home (OR 2.02, 95% CI 1.63-2.52), indoor dining ban (OR 1.62, 95% CI 1.25-2.10), public mask mandate (OR 2.18, 95% CI 1.47-3.23), and severe gathering ban (OR 1.68, 95% CI 1.31-2.16). In mutually adjusted models, odds remained elevated for stay at home (AOR 1.47, 95% CI 1.04-2.07) and public mask mandate (AOR = 2.27, 95% CI 1.51-3.41). Stay at home (OR 2.00, 95% CI 1.53-2.62; AOR 1.89, 95% CI 1.25-2.87) was also associated with greater likelihood of decrease in death velocity in unadjusted and adjusted models. CONCLUSIONS: NPIs employed in the U.S. during the COVID-19 pandemic, most significantly stay at home orders, were associated with decreased COVID-19 burden.