Chemical weed control remains a widely used component of integrated weed management strategies because of its cost-effectiveness and rapid removal of crop pests. Additionally, dicamba-plus-glyphosate mixtures are a commonly recommended herbicide combination to combat herbicide resistance, specifically in recently commercially released dicamba-tolerant soybean and cotton. However, increased spray drift concerns and antagonistic interactions require that the application process be optimized to maximize biological efficacy while minimizing environmental contamination potential. Field research was conducted in 2016, 2017, and 2018 across three locations (Mississippi, Nebraska, and North Dakota) for a total of six site-years. The objectives were to characterize the efficacy of a range of droplet sizes [150 µm (Fine) to 900 µm (Ultra Coarse)] using a dicamba-plus-glyphosate mixture and to create novel weed management recommendations utilizing pulse-width modulation (PWM) sprayer technology. Results across pooled site-years indicated that a droplet size of 395 µm (Coarse) maximized weed mortality from a dicamba-plus-glyphosate mixture at 94 L ha–1. However, droplet size could be increased to 620 µm (Extremely Coarse) to maintain 90% of the maximum weed mortality while further mitigating particle drift potential. Although generalized droplet size recommendations could be created across site-years, optimum droplet sizes within each site-year varied considerably and may be dependent on weed species, geographic location, weather conditions, and herbicide resistance(s) present in the field. The precise, site-specific application of a dicamba-plus-glyphosate mixture using the results of this research will allow applicators to more effectively utilize PWM sprayers, reduce particle drift potential, maintain biological efficacy, and reduce the selection pressure for the evolution of herbicide-resistant weeds.