AbstractPalmer amaranth (Amaranthus palmeri S. Watson) has evolved resistance to herbicides targeting nine sites of action. Phytoene desaturase‐inhibiting herbicides remain among the few sites of action that are still effective in controlling Palmer amaranth. Greenhouse experiments were conducted to evaluate the effectiveness of fluridone and diflufenican in controlling difficult‐to‐control Palmer amaranth accessions collected in Arkansas from 2016 to 2022, to quantify the response of three accessions that exhibited low sensitivity to both herbicides, and to evaluate the effectiveness of photosystem II inhibitors alone and with fluridone or diflufenican on three accessions. At 14 days after a preemergence application, Palmer amaranth control with fluridone and diflufenican ranged from 42% to 100% and 33% to 99% across 23 accessions, respectively. Three accessions required 10.2 to 26.7 times more fluridone than the susceptible Palmer amaranth standard based on LD50 values (where LD50 is the lethal dose to kill 50% of the population), with less than 50% mortality achieved with a 1x herbicide rate for two of the three accessions. For diflufenican, the LD50 values for the three accessions were 3.9–18.5 times greater than the susceptible standard. An additive response for mortality and biomass reduction resulted from adding fluometuron to fluridone at all rates tested. An additive or sometimes a synergistic response occurred with the combinations of metribuzin plus diflufenican. Overall, fluridone exhibited higher efficacy than diflufenican for most accessions tested. While phytoene desaturase‐inhibiting herbicides remain an effective control option for most Palmer amaranth accessions, herbicide mixtures targeting multiple sites of action remain essential for delaying resistance and obtaining effective control of this problematic weed.