The antagonistic effects of water hardness have led to a decrease in herbicides' efficacy, especially in regions where the bedrock is mainly composed of lime and dolomite. In such conditions, tank mixtures of herbicides may improve herbicides' efficacy. Our study evaluated how different agents of water hardness, such as calcium chloride (CaCl 2), magnesium chloride (MgCl 2), iron(III) chloride (FeCl 3), and deionized water (without water hardness), affect the tank mixture of 2,4-D amine and sulfosulfuron in various ratios (0:100, 25:75, 50:50, 75:25, and 100:0). The results showed that the efficacy of both herbicides in decreasing the biomass and survival of flixweed [ Descurainia sophia (L.) Webb ex Prantl] decreased when exposed to water hardness agents. In the case of 2,4-D amine and sulfosulfuron, the presence of water hardness caused by iron(III) chloride resulted in a 45% and 52% increase in the ED 50 of biomass, respectively, compared to the condition without water hardness. The lowest ED 50 values for survival were obtained with deionized water (10.06 g a.i. ha−1), CaCl 2 (39.21 g a.i. ha−1), MgCl 2 (12.08 g a.i. ha−1), and FeCl 3 (36.60 g a.i. ha−1) in different ratios of 2,4-D amine and sulfosulfuron (50:50, 25:75, 50:50, and 25:75). Isobolographic analysis was used to confirm the mixture effects of these herbicides, which corroborated the dose-response findings of this study. Based on the concentration addition and Hewlett models, herbicides' efficacy was higher when used in tank mixing, especially in a 50:50 ratio, compared to using them alone. This study proved that tank mixing these herbicides prevents them from reducing their efficacy in controlling broadleaf weeds such as flixweed in areas with water hardness. In addition, using these herbicides in a tank mixture may be beneficial in delaying the development of herbicide resistance and the shift in weed flora that often occurs when a single herbicide is used. • Water hardness decreased the efficacy of both herbicides in decreasing the biomass and survival of flixweed. • Iron(III) chloride caused the most significant decrease in efficacy. • Tank mixing 75% sulfosulfuron and 25% 2,4-D amine with iron(III) chloride is the most effective in reducing survival by 50%. • The synergistic or antagonistic effects of herbicide mixtures can vary depending on the specific conditions and herbicides used. • The isobole diagrams show the different ratios of the two herbicides and their effects on flixweed biomass. [ABSTRACT FROM AUTHOR]