Mexico City is the second most populated city in Latin America, and it went through two partial lockdowns between April 1 and May 31, 2020 for reducing the COVID-19 propagation. The present study assessed air quality and its association with human mortality rates during the lockdown by estimating changes observed in air pollutants (CO, NO2, O3, SO2, PM10 and PM2.5) between the lockdown (April 1 - May 31) and pre-lockdown (January 1 – March 31) periods, as well as by comparing the air quality data of lockdown period with the same interval of previous five-years (2015-2019). Concentrations of NO2 (-29%), SO2 (-55%) and PM10 (-11%) declined and the contents of CO (+1.1%), PM2.5 (+19%) and O3 (+63%) increased during the lockdown compared to the pre-lockdown period. This study also estimated that NO2, SO2, CO, PM10 and PM2.5 reduced by 19-36%, and O3 enhanced by 14% compared to the average of 2015-2019. Reduction in traffic as well as less emission from vehicle exhausts led to remarkable decline in NO2, SO2 and PM10. The significant positive associations of PM2.5, CO and O3 with the numbers of COVID-19 infections and deaths, however, underscored the necessity to enforce air pollution regulations to protect human health in one of the important cities of the northern hemisphere.