COVID-19 has caused almost 770,000 deaths in the United States by November 2021. The nighttime light (NTL), representing the intensity of human activities, may reflect the degree of human contacts and therefore the intensity of COVID-19 transmission. This study intended to assess the associations between NTL differences and COVID-19 incidence and mortality among U.S. counties. The COVID-19 data of U.S. counties as of 31 December 2020 were collected. The average NTL values for each county in 2019 and 2020 were derived from satellite data. A negative binomial mixed model was adopted to assess the relationships between NTL intensity and COVID-19 incidence and mortality. Compared to the counties with the lowest NTL level (0.14–0.37 nW/cm²/sr), those with the highest NTL level (1.78–59.61 nW/cm²/sr) were related with 15% higher mortality rates (mortality rate ratio:1.15, 95 %CI: 1.02–1.30, p-value: 0.02) and 23% higher incidence rates (incidence rate ratio:1.23, 95 %CI: 1.13–1.34, p-value < 0.0001). Our study suggested that more intensive NTL was related with higher incidence and mortality rates of COVID-19, and NTL had a stronger correlation with the COVID-19 incidence rate than mortality rate. Our findings have contributed solid epidemiological evidence to the existing COVID-19 knowledge pool, and would help policymakers develop interventions when faced with the potential risk of the following outbreaks.