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Recent observation and modeling-based studies have shown how air quality has been positively affected by the containment measures enforced due to the COVID-19 outbreak. This work aims to analyze Lombardy’s NO2 atmospheric concentration during the spring lockdown. The region of Lombardy is known for having the largest number of residents in Italy and high levels of pollution. It is also the region where the first European confinement measures were imposed by the Italian government. The modeling suite composed of CAMx (Comprehensive Air Quality Model with Extensions) and WRF (Weather Research and Forecasting model) provides the setting to compare the atmospheric NO2 concentration from mid-February to the end of March with a business as usual situation. The main interest in this work is to investigate the response of NO2 atmospheric concentration to increasingly reduced road traffic. We can simulate, for the first time, a real circumstance of progressively reduced mobility, as well as validating it with measured air quality data. Focusing on the city of Milan, we found that the decrease in NO2 concentration reflects progressively reduced traffic contraction. In the case of a large traffic abatement (71%), the concentration level is reduced by one third. We also find that industrial activities have a relevant impact on NO2 atmospheric concentration, especially in the provinces of Brescia and Bergamo. This study provides an overview of how incisive policies must be implemented to achieve the set environmental targets and protect human health.