Trifludimoxazin is a protoporphyrinogen oxidase (PPO)-inhibiting herbicide currently under development for preplant burndown and soil-residual weed control in soybean [Glycine max (L.) Merr.] and other crops. Greenhouse dose–response experiments with foliar applications of trifludimoxazin, fomesafen, and saflufenacil were conducted on susceptible and PPO inhibitor–resistant (PPO-R) waterhemp [Amaranthus tuberculatus (Moq.) Sauer] and Palmer amaranth (Amaranthus palmeri S. Watson) biotypes. These PPO-R biotypes contained the PPO2 target-site (TS) mutations ΔG210 (A. tuberculatus and A. palmeri), R128G (A. tuberculatus), and V361A (A. palmeri). The resistant/susceptible (R/S) ratios for fomesafen and saflufenacil ranged from 2.0 to 9.2 across all PPO-R biotypes. In contrast, the response of known PPO inhibitor–susceptible and PPO-R biotypes to trifludimoxazin did not differ within each Amaranthus species. In 2017 and 2018, experiments at the Meigs and Davis Purdue Agriculture Centers were conducted in fields with native A. tuberculatus populations composed of 3% and 30% PPO-R plants (ΔG210 mutation), respectively. At Meigs in 2018, A. tuberculatus control following foliar applications of fomesafen, lactofen, saflufenacil, and trifludimoxazin was greater than 95%. When averaged across the other 3 site-years, applications of 25 g ai ha^–1 trifludimoxazin resulted in 95% control of A. tuberculatus at 28 DAA, while applications of fomesafen (343 g ai ha^–1), lactofen (219 g ai ha^–1), or saflufenacil (25.0 or 50 g ai ha^–1), resulted in 80% to 88% control. Thus, at these relative application rates, the foliar efficacy of trifludimoxazin was comparable or greater on A. tuberculatus when compared with other commercial PPO inhibitors, even in populations where low frequencies of PPO-R plants exist. The lack of cross-resistance for common PPO2 TS mutations to trifludimoxazin and the level of foliar field efficacy observed on populations containing PPO-R individuals suggest that trifludimoxazin may be a valuable herbicide in an integrated approach for managing herbicide-resistant Amaranthus weeds.