Nozzle type and herbicide application timing can affect herbicide efficacy. Prickly sida (Sida spinosa) and barnyardgrass (Echinochloa crus-galli) are problematic weeds in eastern Mississippi cotton production and have reduced yield in recent years. Field studies were conducted at two locations – Brooksville, MS (2018, 2019) and Starkville, MS (2019) to understand the nozzle type and herbicide application timing effects on prickly sida and barnyardgrass control in cotton. Studies also compared applications made by an eight-nozzle tractor-mounted sprayer with a four-nozzle backpack sprayer. Herbicide applications were made at four timings: preemergence (PRE), early-postemergence (EPOST), mid-postemergence (MPOST), and late-postemergence (LPOST) corresponding to the preemergence (immediately after planting), two-to-three leaf, four-to-six leaf, and early-bloom stages, respectively. Treatments were made at 140 l · ha⁻¹ applied at each growth stage, with nozzle type and sprayer as variables by each timing. Results showed no differences in treatments applied with backpack and tractor-mounted sprayers. Control of barnyardgrass was significantly affected by nozzle type, but control of prickly sida was not significantly influenced by nozzle type. In all three site-years, plots receiving a MPOST only herbicide application resulted in less weed control than areas receiving a two-pass POST herbicide program. Cotton yield was significantly affected by the herbicide program at one site-year, but was not significantly affected by the herbicide program except where cotton injury exceeded 15%. A two- or three-pass herbicide program was most effective in controlling prickly sida and barnyardgrass in Mississippi cotton.