Targeted sprayers use artificial intelligence to enable on-the-go weed detection and herbicide application, reducing the need to spray entire fields with foliar herbicides. A targeted sprayer was evaluated for treating weeds in corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] cropping systems in the Midwestern United States. Using a ONE SMART SPRAY sprayer, our objectives were to (1) evaluate the efficacy of different herbicide application programs; two-passes, spot-spray (SS) only, or simultaneous broadcast residual and SS foliar herbicides; (2) determine if weed detection thresholds influence weed control; and (3) determine the cost for each herbicide program compared to a traditional broadcast application. Field experiments were conducted in 2022 and 2023 near Manhattan, KS and in 2023 at Seymour, IL. Both green-on-brown (GOB; burndown applications) and green-on-green (GOG; in-crop applications) were applied. Main plot treatments consisted of four herbicide programs and the split-plot consisted of four weed detection thresholds: herbicide Efficacy, Balanced, Savings, and a Broadcast application. The percentage of area infested with weeds within each plot was estimated visually 42 days after the GOG application. A map was constructed using raw sprayer data to show when nozzles were turned on or off within a sub-plot, an “as-applied map”, and used to determine herbicide program costs based on the percentage of each plot area sprayed. Results indicated that herbicide programs with simultaneous broadcast and SS components, in many cases, resulted in similar area infested with weeds compared with broadcast applications with the same herbicide products. As expected, herbicide costs in SS applications were less than in broadcast applications. The ONE SMART SPRAY sprayer demonstrated potential to reduce herbicide input costs without compromising weed control.