Herbicide applications often do not reach their full potential because only a small amount of the active ingredients reaches the intended targets. Selecting the appropriate application parameters and equipment can allow for improved efficacy. The objective of this research was to evaluate the effect of droplet size on efficacy of six commonly used herbicides. Atrazine (1.12 kg ai ha−1), cloransulam-methyl (0.18 g ai ha−1), dicamba (0.14 kg ae ha−1), glufosinate (0.59 kg ai ha−1), saflufenacil (12.48 g ai ha−1), and 2,4-D (0.20 kg ae ha−1) were applied to seven plant species using an XR11003 nozzle at 138, 276, and 414 kPa and a AI11003 nozzle at 207, 345, and 483 kPa. Each herbicide, nozzle, and pressure combination was evaluated for droplet size spectra. Treatments were applied at 131 L ha−1 to common lambsquarters, common sunflower, shattercane, soybean, tomato, velvetleaf, and volunteer corn. Control from 2,4-D was observed to increase approximately 12% on average for all species except common lambsquarters as droplet size increased from medium to very coarse (Dv0.5 303 to 462 μm; Dv0.5 is droplet size such that 50% of spray volume is contained in droplets of equal or smaller size). Control with atrazine was near 95% for common lambsquarters, common sunflower, and soybean. Atrazine provided the greatest shattercane control using a medium (Dv0.5 325 μm) droplet, whereas the same droplet size provided the lowest tomato control. Control of common lambsquarters, shattercane, and tomato with cloransulam-methyl increased 79% when decreasing droplet size from extremely coarse to fine (Dv0.5 637 to 228 μm). Dicamba control of common lambsquarters increased 17% using a medium droplet compared with a fine droplet (Dv0.5 279 to 204 μm). Dry weight of common sunflower and soybean was reduced 21% using dicamba when using a very coarse spray compared with a fine spray classification (Dv0.5 491 to 204 μm). Common lambsquarters control using glufosinate increased 18% using a fine spray classification (Dv0.5 186 μm) compared with medium (Dv0.5 250 μm) and both very coarse droplet sizes (Dv0.5 470 and 516 μm). Conversely, tomato and velvetleaf control with glufosinate was maximized using a very coarse (Dv0.5 470 and 516 μm) or extremely coarse droplet (Dv0.5 628 μm) with increases of 11 and 25% compared with a fine spray (Dv0.5 186 μm). Saflufenacil control of volunteer corn was 38% greater using extremely coarse droplets (Dv0.5 622 μm) than fine, medium, and very coarse spray classifications (Dv0.5 257 to 514 μm). Overall, spray classifications for the herbicides evaluated play an important role in herbicide efficacy and should be tailored to the herbicide being used and the targeted weed species.