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Restrictions on human activities remarkably reduced emissions of air pollutants in China during the COVID-19 lockdown periods. However, distinct responses of O3 concentrations were observed across China. In the Beijing–Tianjin–Hebei (BTH) and Yangtze River Delta (YRD) regions, O3 concentrations were enhanced by 90.21 and 71.79% from pre-lockdown to lockdown periods in 2020, significantly greater than the equivalent concentrations for the same periods over 2015–2019 (69.99 and 43.62%, p < 0.001). In contrast, a decline was detected (−1.1%) in the Pearl River Delta (PRD) region. To better understand the underlying causes for these inconsistent responses across China, we adopted the least absolute shrinkage and selection operator (Lasso) and ordinary linear squares (OLS) methods in this study. Statistical analysis indicated that a sharp decline in nitrogen dioxide (NO2) was the major driver of enhanced O3 in the BTH region as it is a NOx-saturated region. In the YRD region, season-shift induced changes in the temperature/shortwave radiative flux, while lockdown induced declines in NO2, attributable to the rise in O3. In the PRD region, the slight drop in O3 is attributed to the decreased intensity of radiation. The distinct regimes of the O3 response to the COVID-19 lockdown in China offer important insights into different O3 control strategies across China. [ABSTRACT FROM AUTHOR]