Emerging targeted herbicide application technologies, such as the ONE SMART SPRAY system (a joint venture of Bosch, Gerlingen, Germany; and BASF Corporation, Research Triangle Park, NC), enable postemergence herbicide application only where weeds are detected. Field studies were conducted in 4 site-years in Seymour, Illinois, and Janesville, Wisconsin, during 2023 and 2024 to compare area treated and waterhemp control between broadcast and targeted herbicide applications to soybean. Early postemergence application of herbicides to soybean at the V2 growth stage at the Seymour location in 2023 resulted in less area treated (26%) than when herbicides were applied at the standard time (76%) but required inclusion of a layered residual herbicide to reach 89% to 93% waterhemp control and biomass reduction ≥94% at 28 d after the standard application time (DASAT). The standard herbicide application time (the V4 growth stage of soybean) at the Seymour location in 2023 provided 87% to 97% waterhemp control and ≥94% biomass reduction at 28 DASAT. In 2 site-years, when waterhemp densities were low (≤5 plants m−2), treatments provided >96% waterhemp control and biomass reduction at 28 DASAT, and targeted applications resulted in 17% to 34% area treated, regardless of application time. In contrast, at Janesville in 2024 (high waterhemp density, >30 plants m−2), waterhemp control and biomass reduction did not exceed 90% at 28 DASAT, but the area treated was ≥97% at postemergence application, indicating that targeted spraying essentially functioned as a broadcast application and would have required additional postemergence applications for effective season-long control. Under high waterhemp densities, frequent nozzle activation reduced potential herbicide savings and diminished differences from broadcast applications, clearly indicating that targeted herbicide application systems are best suited for fields where effective foundational management practices, including robust preemergence herbicide applications and other integrated weed management tactics, reduce weed density during postemergence application season.