Palmer amaranth is one of the most problematic weeds in cropping systems of North America, especially in midsouthern United States, because of its competitive ability and propensity to evolve resistance to several herbicide sites of action. Previously, we confirmed and characterized the first case of nontarget site resistance (NTSR) to fomesafen in a Palmer amaranth accession from Randolph County, AR (RCA). The primary basis of the present study was to evaluate the cross- and multiple-resistance profile of the RCA accession. The fomesafen dose-response assay in the presence of malathion revealed a lower level of RCA resistance when compared with fomesafen alone. The resistance index of the RCA accession, based on 50% biomass reduction, ranged from 63-fold (fomesafen alone) to 22-fold (malathion plus fomesafen), when compared with a 2007 susceptible, and 476-fold and 167-fold, respectively, relative to a 1986 susceptible check. The RCA accession was resistant to other protoporphyrinogen oxidase (PPO) inhibitors (i.e., flumioxazin, acifluorfen, saflufenacil) as well as the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor tembotrione and acetolactate synthase (ALS) inhibitor pyrithiobac sodium. Sequencing of the ALS gene revealed no point mutations, indicating that a target-site mechanism is not involved in conferring ALS-inhibitor resistance in the RCA accession. Of the three PPO-inhibiting herbicides tested in combination with the malathion, saflufenacil resulted in the greatest biomass reduction (80%; P < 0.05) and lowest survival rate (23%; P < 0.05) relative to nontreated plants. The application of cytochrome P450 or glutathione S-transferase inhibitors with fomesafen did not lead to any adverse effects on soybean, suggesting a possible role for these compounds for management of NTSR under field conditions. These results shed light on the relative unpredictability of NTSR in conferring herbicide cross- and multiple resistance in Palmer amaranth.