The first goal of this study is to quantify the magnitude and spatial variability of air quality changes in the USA during the COVID-19 pandemic. We focus on two pollutants that are federally regulated, nitrogen dioxide (NO2) and fine particulate matter (PM2.5). NO2 and PM2.5 are both primary and secondary pollutants, meaning that they can be emitted either directly into the atmosphere or indirectly from chemical reactions of emitted precursors. NO2 is emitted during fuel combustion by all motor vehicles and airplanes. PM2.5 is emitted by airplanes and, among motor vehicles, mostly by diesel vehicles, such as commercial heavy-duty diesel trucks. Both PM2.5 and NO2 are also emitted by fossil-fuel power plants, although PM2.5 almost exclusively by coal power plants. Observed concentrations at all available ground monitoring sites (240 and 480 for NO2 and PM2.5, respectively) were compared between April 2020, the month during which the majority of US states had introduced some measure of social distancing (e.g., business and school closures, shelter-in-place, quarantine), and April of the prior 5 years, 2015–2019, as the baseline. Large, statistically significant decreases in NO2 concentrations were found at more than 65% of the monitoring sites, with an average drop of 2 parts per billion (ppb) when compared to the mean of the previous 5 years. The same patterns are confirmed by satellite-derived NO2 column totals from NASA OMI, which showed an average drop in 2020 by 13% over the entire country when compared to the mean of the previous 5 years. PM2.5 concentrations from the ground monitoring sites, however, were not significantly lower in 2020 than those in the past 5 years and were more likely to be higher than lower in April 2020 when compared with those in the previous 5 years. After correcting for the decreasing multi-annual concentration trends, the net effect of COVID-19 at the ground stations in April 2020 was a reduction in NO2 concentrations by − 1.3ppb and a slight increase in PM2.5 concentrations by + 0.28 μg/m3. The second goal of this study is to explain the different responses of these two pollutants, i.e., NO2 was significantly reduced but PM2.5 was nearly unaffected, during the COVID-19 pandemic. The hypothesis put forward is that the shelter-in-place measures affected people’s driving patterns most dramatically, thus passenger vehicle NO2 emissions were reduced. Commercial vehicles (generally diesel) and electricity demand for all purposes remained relatively unchanged, thus PM2.5 concentrations did not drop significantly. To establish a correlation between the observed NO2 changes and the extent to which people were actually sheltering in place, thus driving less, we used a mobility index, which was produced and made public by Descartes Labs. This mobility index aggregates cell phone usage at the county level to capture changes in human movement over time. We found a strong correlation between the observed decreases in NO2 concentrations and decreases in human mobility, with over 4 ppb decreases in the monthly average where mobility was reduced to near 0 and around 1 ppb decrease where mobility was reduced to 20% of normal or less. By contrast, no discernible pattern was detected between mobility and PM2.5 concentrations changes, suggesting that decreases in personal-vehicle traffic alone may not be effective at reducing PM2.5 pollution.