Glyphosate-resistant Palmer amaranth (Amaranthus palmeri S. Wats.) is a widespread problem in cotton (Gossypium hirsutum L.) production. Growers are encouraged to include residual herbicides applied preemergence (PRE) and postemergence (POST) in their management systems to control this weed adequately. Pyroxasulfone, an isoxazoline herbicide with the same mode of action as acetochlor and S-metolachlor, effectively controls Palmer amaranth in corn (Zea mays L.) and soybean [Glycine max (L.) Merr.]. The objective of this study was to compare cotton tolerance and Palmer amaranth control with pyroxasulfone, acetochlor, and S-metolachlor applied PRE and POST to cotton. Treatments in a field study at four locations included pyroxasulfone at 60, 90, and 120 g a.i. ha-1 applied PRE or mixed with glyphosate and applied POST; an encapsulated formulation of acetochlor at 1260 g a.i. ha-1 applied PRE or POST with glyphosate; and S-metolachlor at 1070 g a.i. ha-1 applied POST with glyphosate. Pyroxasulfone PRE increased late-season Palmer amaranth control 14 to 27% and increased yield in one of two years. Similar results were observed with pyroxasulfone and acetochlor applied PRE. Pyroxasulfone, acetochlor, and S-metolachlor applied POST with glyphosate did not increase Palmer amaranth control compared with glyphosate alone. Cotton was less tolerant of pyroxasulfone applied PRE or POST than acetochlor applied PRE or POST or S-metolachlor applied POST. Cotton growth was reduced 14 to 17% by pyroxasulfone applied PRE and stand was reduced 10 to 25%. Acetochlor PRE reduced cotton growth 6% but did not affect stand. Pyroxasulfone applied POST caused 23 to 36% necrosis 7 d after application and reduced cotton growth 21 to 39% at 14 d after application compared with 6 to 17% necrosis and 3 to 8% growth reduction caused by acetochlor and S-metolachlor. Yields were not reduced by any treatment.