During the winter of 2019, the global outbreak of COVID-19 prompted extensive research on urban air pollution under lockdown measures. However, these studies predominantly focused on winter conditions, thereby limiting investigations into changes in urban air pollutants during other seasons that were also subject to lockdown restrictions. Shanghai, China, has undergone two COVID-19 lockdown periods in two seasons: winter 2019 and spring 2022. The seasonal variations and human activities were represented by meteorological factors and nighttime light brightness in this paper, respectively. The reduction in human-related emissions during the two lockdown periods was estimated based on the targets outlined in China’s Air Pollution Prevention and Control Action Plan. The results showed significant reductions in NO2 and PM particles during the two lockdown periods, both accompanied by a notable increase in O3 concentration. In comparison to the winter lockdown, there was an approximate 40% decrease in the NO2 and PM2.5 concentrations in the spring, while the O3 concentration exhibited an increase of 48.81%. Furthermore, due to shifting wind patterns during the two lockdowns from winter to spring, the high-pollution core areas shifted 20–25 km southeastward in the spring. The PM particles and NO2 concentrations exhibited a considerable impact from human activities, whereas the O3 concentration was affected mostly by seasonal change and interactions among air pollutants. Compared to the corresponding non-lockdown condition, the concentration of CO decreased during the winter lockdown; however, it increased during the spring lockdown. The different change in CO concentration during the two lockdown periods was found to have a lower effect on the O3 concentration than that caused by changes in meteorological factors and nitrogen oxide (NO, NO2) concentrations. In summary, the impact of COVID-19 lockdown periods on urban air pollutants was more pronounced in spring compared to winter, and the interactions among air pollutants also underwent alterations.