Due in part to climate change, wildfire activity is increasing, with the potential for greater public health impact from smoke in downwind communities. Studies examining the health effects of wildfire smoke have focused primarily on fine particulate matter (PM2.5), but there is a need to better characterize other constituents, such as hazardous air pollutants (HAPs). HAPs are chemicals known or suspected to cause cancer or other serious health effects that are regulated by the United States (US) Environmental Protection Agency. Here, we analyzed concentrations of 21 HAPs in wildfire smoke from 2006 to 2020 at 309 monitors across the western US. Additionally, we examined HAP concentrations measured in a major population center (San Jose, CA) affected by multiple fires from 2017 to 2020. We found that concentrations of select HAPs, namely acetaldehyde, acrolein, chloroform, formaldehyde, manganese, and tetrachloroethylene, were all significantly elevated on smoke-impacted versus nonsmoke days (P < 0.05). The largest median increase on smoke-impacted days was observed for formaldehyde, 1.3 μg/m3 (43%) higher than that on nonsmoke days. Acetaldehyde increased 0.73 μg/m3 (36%), and acrolein increased 0.14 μg/m3 (34%). By better characterizing these chemicals in wildfire smoke, we anticipate that this research will aid efforts to reduce exposures in downwind communities.