<p>Policies designed to reduce transportation emissions are known to be co-beneficial due to reductions in planet-warming greenhouse gases like carbon dioxide (CO₂) and health-harmful air pollutants, such as nitrogen dioxide (NO₂). The growing recognition of persistent racial and ethnic disparities in air pollution exposure and associated health impacts has increased demand for policy interventions aimed at systematically reducing such inequities. Here, we use a regulatory-grade air quality model focused on the Chicago region to find that medium- and heavy-duty vehicle (MHDV) tailpipe emissions account for ∼22% of the area’s ambient NO₂ concentrations. Exposure to MHDV-tailpipe NO₂ in our domain is associated with 1330 (95% confidence interval (CI): 330, 2000) annual premature deaths and 1580 (95% CI: −310, 3870) new cases of pediatric asthma, disproportionately affecting census tracts with higher percentages of residents of color. Given the inequitable impacts of MHDV NO₂ exposure, we also use our model to assess the air quality, health, and equity outcomes if a policy scenario based on California’s Advanced Clean Trucks (ACT) regulation were instantaneously adopted in Illinois. We find that ACT adoption would lead to ∼48% of on-road MHDVs having zero tailpipe emissions by 2050; an instantaneous transition to this policy would reduce annual mean population-weighted NO₂ concentrations by 0.98 ppb (parts per billion) (−8.4%), resulting in reductions of 500 (95% CI: −120, −750) premature deaths and 600 (95% CI: 120, −1440) fewer new pediatric asthma cases annually–with the largest health benefits observed in neighborhoods with higher percentages of residents of color. Our study highlights the benefits of implementing policy interventions focused on zero-emission MHDVs to address air pollution exposure and health impact disparities.</p>