Cotton production in the Texas High Plains faces significant challenges due to water scarcity resulting from uneven rainfall patterns and declining levels of the Ogallala Aquifer. Deficit or reduced irrigation is one of the most common water management strategies to increase water use efficiency and cotton productivity in the region. However, deficit irrigation can affect the efficacy of herbicides on weeds. This study investigates how varying irrigation levels affect herbicide efficacy on weeds in cotton production systems. A 2-yr field study was conducted at Texas Tech University Quaker Research Farm in 2023 and 2024. The experiment was randomized three times in a split-plot design with two irrigation levels: I1 (100% crop evapotranspiration [ETc] replacement) and I2 (50% ETc replacement) as the main plot factor and different preemergent and postemergent herbicide combinations as the subplot factor. Results indicated that reducing the irrigation level to I2 did not affect the total weed density or biomass production but resulted in decreased Palmer amaranth height and biomass production compared to I1. Among herbicide treatments, acetochlor, prometryn, or S-metolachlor applied preemergence followed by glyphosate + acetochlor, prometryn, or S-metolachlor applied postemergence provided the most effective weed control, reducing total weed density, Palmer amaranth weed density, and biomass compared with the untreated control and to preemergence herbicides applied alone. Although I2 resulted in lower plant height in both years than I1, it produced comparable cotton biomass and lint yield. Among the herbicide treatments, a preemergence application followed by a postemergence application of glyphosate + residual herbicide yielded significantly higher lint yield than the untreated control in both years. In conclusion, the study demonstrates that deficit irrigation is an effective water conservation technique that maintains cotton yield and herbicide efficacy. Additionally, using preemergence fb postemergence herbicide combinations, farmers can achieve effective weed control and sustain cotton productivity in semiarid regions.