Wuhan was the primary city in the world to adopt lockdown measures during the Coronavirus Disease 2019 pandemic. The influence of the abrupt halt of human activities on the air quality of Wuhan is a subject of considerable attention. This study is based on air quality data from 21 monitoring stations in Wuhan from 2016 to 2020. The lag effect and seasonal factors of AQI were taken into account to analyze the changes in air quality in Wuhan under the influence of the pandemic blockade. The results showed the following during the city closure: (1) A lagging effect is observed in air quality changes, with the change point occurring on the 14th day after the city closure; (2) the air quality index is substantially decreased, demonstrating a reduction in spatial differences; (3) NO2, PM10, and PM2.5 significantly decreased whilst O3 increased, and SO2 and CO did not change significantly; (4) except for the insignificant changes in spatial differences of PM10, all pollutants demonstrated a changing pattern of decreasing geographical differences. This paper provides a reference for studying the influence of human activities on the natural environment.