With the spread of COVID-19 pandemic worldwide, the Government of India had imposed lockdown in the month of March 2020 to curb the spread of the virus furthermore. This shutdown led to closure of various institutions, organizations, and industries, and restriction on public movement was also inflicted which paved way to better air quality due to reduction in various industrial and vehicular emissions. To brace this, the present study was carried out to statistically analyze the changes in air quality from pre-lockdown period to unlock 6.0 in South Indian cities, namely, Bangalore, Chennai, Coimbatore, and Hyderabad, by assessing the variation in concentration of PM2.5, PM10, NO2, and SO2 during pre-lockdown, lockdown, and unlock phases. Pollutant concentration data was obtained for the selected timeframe (01 March 2020-30 November 2020) from CPCB, and line graph was plotted which had shown visible variation in the concentration of pollutants in cities taken into consideration. Analysis of variance (ANOVA) was applied to determine the mean differences in the concentration of pollutants during eleven timeframes, and the results indicated a significant difference (F (10,264) = 3.389, p < 0.001). A significant decrease in the levels of PM2.5, PM10, NO2, and SO2 during the lockdown phases was asserted by Tukey HSD results in Bangalore, Coimbatore, and Hyderabad stations, whereas PM10 and NO2 significantly increased during lockdown period in Chennai station. In order to understand the cause of variation in the concentration of pollutants and to find the association of pollutants with meteorological parameters, the Pearson correlation coefficient was used to study the relationship between PM2.5, PM10, NO2, and SO2 concentrations, temperature, rainfall, and wind speed for a span of 15months, i.e., from January 2020 to March 2021. At a significant level of 99.9%, 99%, and 95%, a significant correlation among the pollutants, rainfall had a major impact on the pollutant concentration in Bangalore, Coimbatore, Hyderabad, and Chennai followed by wind speed and temperature. No significant influence of temperature on the concentration of pollutants was observed in Bangalore station.