Palmer amaranth has developed resistance to at least seven herbicide sites of action in the Cotton Belt of the United States, leaving producers with fewer options to manage this weed. Previous research with corn and newly commercially released soybean systems have found the use of 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicides such as isoxaflutole (IFT) to be effective at managing Palmer amaranth. Consequently, a new transgenic cultivar of cotton is being developed with tolerance to IFT, allowing for in-crop applications of the herbicide. Two separate studies were conducted near Marianna, AR, in 2019 and replicated in 2020, to investigate the crop safety and utility of IFT when added to cotton herbicide programs. Herbicide programs featured IFT as a preemergence or early-postemergence option, residual herbicides in subsequent postemergence applications, and the presence or absence of a layby application. The use of IFT did not significantly impact cotton injury or yield, whereas the use of layered residual herbicides, including IFT, increased Palmer amaranth control compared to those without. Regardless of earlier use of IFT, layby applications were needed for season-long control of Palmer amaranth, entireleaf morningglory, broadleaf signalgrass, and johnsongrass, as evidenced by greater than a 20 percentage point improvement in control of all weeds when a layby application was made. Overall, findings from these studies indicate IFT to be a suitable tool for managing Palmer amaranth and will provide an additional site of action for cotton herbicide programs. Sequential herbicide applications and overlaying residuals were found to be paramount for managing Palmer amaranth throughout the season.