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Abstract Background The Coronavirus Disease 2019 (COVID-19) pandemic warranted a myriad of government-ordered business closures across the USA in efforts to mitigate the spread of the virus. This study aims to discover the implications of government-enforced health policies of reopening public businesses amidst the pandemic and its effect on county-level infection rates. Methods Eighty-three US counties (n = 83) that reported at least 20 000 cases as of 4 November 2020 were selected for this study. The dates when businesses (restaurants, bars, retail, gyms, salons/barbers and public schools) partially and fully reopened, as well as infection rates on the 1st and 14th days following each businesses’ reopening, were recorded. Regression analysis was conducted to deduce potential associations between the 14-day change in infection rate and mask usage frequency, median household income, population density and social distancing. Results On average, infection rates rose significantly as businesses reopened. The average 14-day change in infection rate was higher for fully reopened businesses (infection rate = +0.100) compared to partially reopened businesses (infection rate = +0.0454). The P-value of the two distributions was 0.001692, indicating statistical significance (P < 0.01). Conclusion This research provides insight into the transmission of COVID-19 and promotes evidence-driven policymaking for disease prevention and community health.