Recent concerns regarding herbicide spray drift, its subsequent effect on the surrounding environment, and herbicide efficacy have prompted applicators to focus on methods to reduce off-target movement of herbicides. Herbicide applications are complex processes, and as such, few studies have been conducted that consider multiple variables that affect the droplet spectrum of herbicide sprays. The objective of this study was to evaluate the effects of nozzle type, orifice size, herbicide active ingredient, pressure, and carrier volume on the droplet spectra of the herbicide spray. Droplet spectrum data were collected on 720 combinations of spray-application variables, which included six spray solutions (five herbicides and water alone), four carrier volumes, five nozzles, two orifice sizes, and three operating pressures. The laboratory study was conducted using a Sympatec laser diffraction instrument to determine the droplet spectrum characteristics of each treatment combination. When averaged over each main effect, nozzle type had the greatest effect on droplet size. Droplet size rankings for nozzles, ranked smallest to largest using volume median diameter (Dv0.5) values, were the XR, TT, AIXR, AI, and TTI nozzle with 176% change in Dv0.5 values from the XR to the TTI nozzle. On average, increasing the nozzle orifice size from a 11003 orifice to a 11005 increased the Dv0.5 values 8%. When compared with the water treatment, cloransulam (FirstRate) did not change the Dv0.5 value. Clethodim (Select Max), glyphosate (Roundup PowerMax), lactofen (Cobra), and glufosinate (Ignite) all reduced the Dv0.5 value 5, 11, 11, and 18%, respectively, when compared with water averaged over the other variables. Increasing the pressure of AIXR, TT, TTI, and XR nozzles from 138 to 276 kPa and the AI nozzle from 276 to 414 kPa decreased the Dv0.5 value 25%. Increasing the pressure from 276 to 414 kPa and from 414 to 552 kPa for the same nozzle group and AI nozzle decreased the Dv0.5 value 14%. Carrier volume had the least effect on the Dv0.5 value. Increasing the carrier volume from 47 to 187 L ha−1 increased the Dv0.5 value 5%, indicating that droplet size of the herbicides tested were not highly dependent on delivery volume. The effect on droplet size of the variables examined in this study from greatest effect to least effect were nozzle, operating pressure, herbicide, nozzle orifice size, and carrier volume.