Carrier water pH, hardness, coapplied foliar fertilizer, water conditioning agents, and plant height are critical considerations for optimum herbicide performance. Field studies were conducted to evaluate the effect of carrier water pH (4, 6.5, and 9) and zinc (Zn) or manganese (Mn) foliar fertilizer on mesotrione for horseweed and Palmer amaranth control. Additionally, effect of carrier water pH and foliar fertilizer was evaluated on 7.5-, 12.5-, and 17.5-cm tall horseweed. Greenhouse treatments consisted of carrier water pH and foliar fertilizer (Zn, Mn, or without fertilizer); or water hardness (0 to 1,000 mg L−1) in the presence or absence of ammonium sulfate (AMS) for mesotrione control of giant ragweed, horseweed, and Palmer amaranth. Mesotrione activity was greater on horseweed with carrier water pH 6.5 compared to pH 4 or 9. Coapplied Zn fertilizer reduced mesotrione activity on Palmer amaranth in the field study in 2014 and horseweed in the greenhouse study. Mesotrione efficacy was greatly influenced by horseweed height. Percent control ranged from 96 to 99%, 75 to 89%, or 61 to 64% with mesotrione applied on 7.5-, 12.5-, or 17.5-cm tall horseweed, respectively, and results were similar for plant height and dry weight reduction. Increasing carrier water hardness from 0 to 1,000 mg L−1 reduced mesotrione efficacy 28, 18, and 18% (or greater) on giant ragweed, horseweed, and Palmer amaranth, respectively. The addition of AMS enhanced mesotrione efficacy 9, 6, or 9% (or greater) for giant ragweed, horseweed, and Palmer amaranth control, respectively. Mesotrione should be applied at near neutral carrier water pH, hardness < 200 mg L−1, and with AMS for achieving optimum weed control.