Commercial targeted sprayer systems allow producers to reduce herbicide inputs but risks the possibility of not treating emerging weeds. Currently, targeted applications with the John Deere system have five spray sensitivity settings, and no published literature discusses the effects of these settings on detecting and spraying weeds of varying species, sizes, and positions in crops. Research was conducted in Arkansas, Illinois, Indiana, Mississippi, and North Carolina on plantings of corn, cotton, and soybean to determine how various factors might influence the ability of targeted applications to treat weeds. These data included 21 weed species aggregated to six classes with height, width, and densities ranging from 25 to 0.25 cm, 25 to 0.25 cm, and 14.3 to 0.04 plants m−2, respectively. Crop and weed density did not influence the likelihood of treating the weeds. As expected, the sensitivity setting alters the ability to treat weeds. Targeted applications (across sensitivity settings, median weed height and width, and density of 2.4 plants m−2) resulted in a treatment success of 99.6% to 84.4% for Convolvulaceae, 99.1% to 68.8% for decumbent broadleaf weeds, 98.9% to 62.9% for Malvaceae, 99.1% to 70.3% for Poaceae, 98.0% to 48.3% for Amaranthaceae, and 98.5% to 55.8% for yellow nutsedge. Reducing the sensitivity setting reduced the ability to treat weeds. The size of weeds aided targeted application success, with larger weeds being more readily treated through easier detection. Based on these findings, various conditions can affect the outcome of targeted multinozzle applications. Additionally, the analyses highlight some of the parameters to consider when using these technologies.