Since the introduction of West Nile virus (WNV) to the United States over 20 years ago, thousands of cases of human disease and death have been reported. Yearly seasonal outbreaks continue to persist, and the city and suburbs of Chicago, Illinois, is considered a “hot spot” for WNV activity. To interrupt WNV transmission, ground ultra-low volume (ULV) adulticide applications are regularly used to reduce Culex pipiens L. and Culex restuans Theobold (Diptera: Culicidae) abundance and infection. The real-world effectiveness of adulticide applications has not been comprehensively assessed, and prior studies, including our own investigation, have yielded inconclusive or conflicting results. Therefore, we expanded our prior work and evaluated the effects of 5 sequential weekly truck-mounted ULV adulticide applications in large residential areas in the northern suburbs of Chicago, Illinois, in 2019 and 2020. Each day, Cx. pipiens and Cx. restuans host-seeking and gravid mosquitoes were collected to assess abundance, age structure, and WNV infection rates. Adulticide applications resulted in significant reductions of both host-seeking and gravid abundance on the night of treatment. The reduction in host-seeking mosquitoes was followed by a reduction in gravid mosquitoes trapped 3 and 4 days after adulticide application and an increase in the proportion of nulliparous mosquitoes. WNV infection rates were significantly reduced in treatment sites as compared to untreated sites when infection rates were higher in 2020. This large-scale study provides comprehensive evidence that ground ULV adulticide applications are an effective tool in an integrated mosquito management program for combating WNV vectors and infection risk.