The continued development of herbicide-resistant weeds, such as Palmer amaranth, represents a growing concern across the United States Cotton Belt. To mitigate this issue, BASF Corporation developed Axant™ Flex cotton, the first quadruple-stacked herbicide resistance germplasm to improve the control of troublesome weed species in cotton. Field studies were conducted in 2022 and 2023 at the Texas Tech University Research Farm near New Deal, TX, to evaluate the response of Axant Flex cotton to topramezone applied alone or in combinations when applied to 3-leaf cotton (early-postemergence (EPOST)) or to 7-leaf cotton (mid-postemergence (MPOST)). No difference in cotton stand was observed between isoxaflutole or prometryn PRE treatments compared to the nontreated control. In 2022, no EPOST treatment caused greater than 6% crop response at 7 and 14 d after application (DAA). When treatments were made to 7-leaf cotton, crop response did not exceed 18% at 7 and 14 DAA. In 2023, crop response was ≤ 2% at 28 DAA regardless of application timing. No differences in lint yield were observed following any herbicide treatment when compared to the nontreated control in either year. Additionally, fiber length and strength were not adversely affected by treatments containing topramezone EPOST or MPOST in 2022 and 2023. These results support the potential use of topramezone in Axant Flex cotton to help manage troublesome weeds without detrimental effects on yield and fiber quality.