Trifludimoxazin is a novel protoporphyrinogen oxidase (PPO)-inhibiting herbicide currently under development for foliar and residual control of several problematic weeds in preplant applications for soybean production. Field experiments were conducted in 2017 and 2018 to evaluate the foliar efficacy of trifludimoxazin applied alone and in combination with other herbicides on waterhemp, giant ragweed, and horseweed. Foliar applications of trifludimoxazin alone at 12.5 or 25 g ai ha-1 were highly efficacious on glyphosate-resistant waterhemp (94 to 99% control, respectively), moderately effective on giant ragweed (78 to 79% control, respectively), and resulted in minor efficacy on horseweed (≤ 20% control). Combinations of trifludimoxazin with glufosinate, glyphosate, paraquat, or saflufenacil remained highly effective (≥ 91% control) on waterhemp and giant ragweed. All herbicide mixtures with trifludimoxazin applied to horseweed were classified as additive interactions. Greenhouse experiments and Isobole analysis indicated trifludimoxazin mixtures with glyphosate and glufosinate on waterhemp and giant ragweed were additive. Mixtures of trifludimoxazin plus paraquat were slightly antagonistic under greenhouse conditions when applied to either waterhemp or giant ragweed, whereas trifludimoxazin plus saflufenacil was synergistic when applied to giant ragweed. Overall, trifludimoxazin applied alone at 12.5 or 25 g ha-1 was effective for managing waterhemp, and to an extent, giant ragweed, but not horseweed in preplant burndown applications. Furthermore, the addition of glufosinate, glyphosate, paraquat, or saflufenacil to applications of trifludimoxazin does not appreciably reduce weed control for these mixtures. As such, applications of trifludimoxazin alone and in combination with these herbicides may be utilized for effective preplant management of several problematic weeds in soybean.