BackgroundThe outbreak of coronavirus disease (COVID-19) began in Wuhan, China in December 2019 and was declared a global pandemic on 11 March 2020. This study aimed to assess the effects of temperature and long-term exposure to air pollution on the COVID-19 mortality rate at the sub-national level in France.MethodsThis cross-sectional study considered different periods of the COVID-19 pandemic from May to December 2020. It included 96 departments (or NUTS 3) in mainland France. Data on long-term exposure to particulate matter (PM2.5), annual mean temperature, health services, health risk, and socio-spatial factors were used as covariates in negative binomial regression analysis to assess their influence on the COVID-19 mortality rate. All data were obtained from open-access sources.ResultsThe cumulative COVID-19 mortality rate by department increased during the study period in metropolitan France—from 19.8/100,000 inhabitants (standard deviation (SD): 20.1) on 1 May 2020, to 65.4/100,000 inhabitants (SD: 39.4) on 31 December 2020. The rate was the highest in the departments where the annual average of long-term exposure to PM2.5 was high. The negative binomial regression models showed that a 1 μg/m3 increase in the annual average PM2.5 concentration was associated with a statistically significant increase in the COVID-19 mortality rate, corresponding to 24.4%, 25.8%, 26.4%, 26.7%, 27.1%, 25.8%, and 15.1% in May, June, July, August, September, October, and November, respectively. This association was no longer significant on 1 and 31 December 2020. The association between temperature and the COVID-19 mortality rate was only significant on 1 November, 1 December, and 31 December 2020. An increase of 1 °C in the average temperature was associated with a decrease in the COVID-19-mortality rate, corresponding to 9.7%, 13.3%, and 14.5% on 1 November, 1 December, and 31 December 2020, respectively.ConclusionThis study found significant associations between the COVID-19 mortality rate and long-term exposure to air pollution and temperature. However, these associations tended to decrease with the persistence of the pandemic and massive spread of the disease across the entire country.