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Abstract The use of unmanned aerial vehicles (UAVs) shows promise as a potential new method of herbicide application; however, relatively few studies have been conducted to determine how UAV application parameters influence spray deposition and weed control. Separate experiments were conducted in soybean fields in 2023 and 2024 to: 1) compare weed control, spray coverage, and uniformity, and off-target movement between a DJI Agras T40 and ground-based sprayers, and 2) determine the effects of application speed, spray height, and spray volume on spray coverage and waterhemp control with a UAV. Ground-based sprayers consistently provided greater and more uniform spray coverage than the UAV and resulted in more consistent waterhemp control across the swath width. Normalized coverage data indicated greater proportional off-target spray movement with the UAV, although absolute off-target coverage did not differ between application methods. In the second experiment, a variety of different UAV spray application parameters were assessed for their effects on spray coverage and waterhemp control following applications of glufosinate. Coverage in the center of the swath was improved at an application speed of 3.5 m s -1 compared to 7 m s -1 , while increasing the height of application above the soybean canopy from 3 to 4.5 m resulted in lower waterhemp control. Overall, results from this research indicate that UAV applications can provide effective weed control under optimized operating conditions but would require narrower swath widths, careful management of application parameters, and additional drift mitigation practices.